CFGparadigms - User contributions [en]

Ficolins/Mannose-binding protein

2011-04-04T11:50:06Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for mannose-binding protein result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that were first identified in ''Saccharomyces cerevisiae''.<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===
Probes for mouse and human MBP have been included in all versions of the CFG glycogene chip.
 

=== Knockout mouse lines ===
Mice, unlike humans, have two genes encoding MBP: MBP-A and MBP-C. The CFG did not generate mice deficient in these genes, as the double knockout was published in 2004 <ref>Shi L, Takahashi K, Dundee J, Shahroor-Karni S, Thiel S, Jensenius JC, Gad F,
Hamblin MR, Sastry KN, Ezekowitz RA. Mannose-binding lectin-deficient mice are
susceptible to infection with Staphylococcus aureus. J Exp Med. 2004 May
17;199(10):1379-90. PubMed PMID: 15148336; PubMed Central PMCID: PMC2211809.
</ref>. These mice display increased susceptibility to infection by certain pathogens, including ''Staphylococcus aureus'' and ''Pseudomonas aeruginosa''; a reduced inflammatory response; and resistance to ischemia/reperfusion injury <ref>Takahashi K: Lessons learned from murine models of mannose-binding lectin deficiency. Biochem Soc Transact 2008, 36:1487-1490.</ref>.
 

=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:51:16Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for mannose-binding protein result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that were first identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:50:06Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for mannose-binding protein result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:49:47Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for mannose-*binding protein result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:49:04Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for DC-SIGN result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:47:23Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
Glycans on viruses 
High mannose oligosaccharides on viral envelope proteins that are ligands for DC-SIGN result from incomplete processing of glycans in the pathway for biosynthesis of complex N-linked glycans ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp?slideNumber=default GT Database]).
 
Glycans on bacteria 
The biosynthesis pathways for the bacterial lipopolysaccharides have been extensively studied and the gene families responsible for the expression of different glycan sequences have been characterized.<ref name”Raetz2002”>Raetz CR and Whitfield C (2002) Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 71, 635-700</ref>
 
The mycobacterial transferases for synthesis of the lipo-arabinomannan (LAM) core and the extended ManLAM structures have been characterized.<ref name”Tam2009”>Tam, P-H and Lowary, TL (2009) Recent advances in mycobacterial cell wall glycan biosynthesis. Cur. Opin Struct. Biol. 13, 618-625</ref>
 
Glycans on fungi 
The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:45:38Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
 The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".<ref>Douglas CM, Foor F, Marrinan JA, Morin N, Nielsen JB, Dahl AM, Mazur P, Baginsky W, Li W, el-Sherbeini M, Clemas JA, Mandala SM, Frommer BR, Kurz MB (1994) The Saccharomyces cerevisiae FKS1 (ETG1) gene encodes an integral membrane protein which is a subunit of 1,3-beta-D-glucan synthase. Proc Natl Acad Sci U S A 91:12907-11</ref><ref>Mazur P, Morin N, Baginsky W, el-Sherbeini M, Clemas JA, Nielsen JB, Foor F. (1995) Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase. Mol Cell Biol. 15:5671-81</ref><ref>Qadota H, Python CP, Inoue SB, Arisawa M, Anraku Y, Zheng Y, Watanabe T, Levin DE, Ohya Y (1996) Identification of yeast Rho1p GTPase as a regulatory subunit of 1,3-beta-glucan synthase. Science 272:279-81</ref>

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2011-03-25T07:35:32Z

Nicole Thielens: /* Biosynthesis of ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins A and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about ficolins and mannose-binding protein, their carbohydrate ligands, and how they interact with ligands to mediate cell communication. Further information can be found in the GBP Molecule Pages for [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Ctlect_227&sideMenu=no human] and [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_mou_Ctlect_169&sideMenu=no mouse] mannose-binding protein in the CFG database.
=== Carbohydrate ligands ===

L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285:6612-22</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6</ref>. H-ficolin does not bind to any of the glycans.

Mannose-binding protein, also known as mannan-binding lectin (MBL), binds to terminal mannose, fucose and GlcNAc residues on the outer surfaces of bacterial and fungal cell walls. MBL belongs to a family of soluble immune proteins known as the collectins that consist of N-terminal collagen tail regions and C-terminal C-type lectin domains. Other family members include lung surfactant protein A (SP-A) that preferentially binds to galactose, mannose and fucose residues on microbial glycolipids <ref>Childs RA, Wright JR, Ross GF, Yuen CT, Lawson AM, Chai W, Drickamer K, Feizi T (1992) Specificity of lung surfactant protein SP-A for both the carbohydrate and the lipid moieties of certain neutral glycolipids. J Biol Chem 267:9972-9</ref>, and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. <ref>Shrive AK, Martin C, Burns I, Paterson JM, Martin JD, Townsend JP, Waters P, Clark HW, Kishore U, Reid KB, Greenhough TJ (2009) Structural characterisation of ligand-binding determinants in human lung surfactant protein D: influence of Asp325. J Mol Biol 394:776-88.</ref>

Ficolins and mannose-binding protein share the ability to associate with mannan-binding lectin-associated serine protease-2.

=== Cellular expression of GBP and ligands ===

Mannose-binding protein is produced mostly by hepatocytes and secreted into the circulation. SP-A and SP-D are produced mostly by alveolar cells and secreted to the pulmonary surfactant that lines the lung.
 L- and H-ficolins are serum proteins that are essentially synthesized in the liver. H-ficolin is also synthesized by bile duct epithelial cells, by lung ciliated bronchial and type II alveolar epithelial cells, and by glioma cells <ref> Akaiwa M, Yae Y, Sugimoto R, Suzuki SO, Iwaki T, Izuhara K, Hamasaki N (1999) Hakata antigen, a new member of the ficolin/opsonin p35 family, is a novel human lectin secreted into bronchus/alveolus and bile. Histochem Cytochem 47:777-86</ref><ref> Kuraya M, Matsushita M, Endo Y, Thiel S, Fujita T (2003) Expression of H-ficolin/Hakata antigen, mannose-binding lectin-associated serine protease (MASP)-1 and MASP-3 by human glioma cell line T98G. Int Immunol 2003:15:109-17</ref>.

L-ficolin recognizes ligands on several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''.

=== Biosynthesis of ligands ===
 The polysaccharide beta(1,3)-D-glucan is a component of the cell wall of many fungi. The linear polymer is synthesized from UDP-glucose (UDGG) by the multisubunit enzyme UDP-glucose beta(1,3)-D-glucan beta(3)-D-glucosyltransferase. This enzymatic complex contains two catalytic and one regulatory subunits that werefirst identified in "S. cerevisiae".

=== Structure ===

The 3-D structures of the trimeric fibrinogen-like recognition domains of L- and H-ficolins have been solved by X-ray crystallography, revealing similar three-lobed clover-like assemblies, whereas different recognition mechanisms have been deciphered from the structure of complexes with various ligands<ref> Garlatti V, Belloy N, Martin L, Lacroix M, Matsushita M, Endo Y, Fujita T, Fontecilla-Camps JC, Arlaud GJ, Thielens NM, Gaboriaud C (2007) Structural insights into the innate immune recognition specificities of L- and H-ficolins. EMBO J 26:623-33</ref>. An external ligand binding site able to accommodate neutral carbohydrates such as galactose and D-fucose has been identified for H-ficolin. In contrast, L-ficolin exhibited three additional binding sites which define a continuous recognition surface able to bind acetylated and neutral carbohydrates in the context of extended polysaccharides such as 1,3-β-D-glucan.

=== Biological roles of GBP-ligand interaction ===

Ficolins share with mannan-binding lectin the ability to associate with mannan-binding lectin-
associated serine protease-2, thus triggering activation of the lectin complement pathway upon binding to suitable targets and enhancing their phagocytosis. L-ficolin recognizes several strains of opportunistic capsulated bacteria and ''Salmonella typhimurium'' whereas H-ficolin specifically recognizes ''Aerococcus viridans''. In addition to pathogenic microorganisms, L- ficolin binds specifically to apoptotic HL60, U937 and Jurkat T cells, whereas binding of H-ficolin is restricted to apoptotic Jurkat T cells <ref>Kuraya M, Ming Z, Liu X, Matsushita M, Fujita T (2005) Specific binding of L-ficolin and H-ficolin to apoptotic cells leads to complement activation. Immunobiology 209:689-97</ref><ref>Honoré C, Hummelshoj T, Hansen BE, Madsen HO, Eggleton P, Garred P(2007) The innate immune component ficolin 3 (Hakata antigen) mediates the clearance of late apoptotic cells. Arthritis Rheum 56:1598-1607</ref><ref> Jensen ML, Honoré C, Hummelshøj T, Hansen BE, Madsen HO, Garred P(2007) Ficolin-2 recognizes DNA and participates in the clearance of dying host cells. Mol Immunol 44:856-65</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding protein].

=== Glycan profiling ===
Because L and H ficolin and mannose-binding protein bind ligands on bacteria and other micro-organisms, profiling of mammalian glycans is not relevant for these proteins.
 

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.
 Investigators have used CFG glycan arrays to study ligand binding specificity of human L-ficolin (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_609_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_611_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1604 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2121 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2122 here]) and of its rat homologue ficolin A (see example [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1707 here]).
Several analyses with human H-ficolin, which has no homologue in rodents, yielded inconclusive results (see examples [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_PA_v2.1_610_10172006 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1511 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1603 here],
[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1950 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2120 here]). See all glycan array results for ficolin [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh here].

== Related GBPs ==
Serum mannose-binding protein ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=Mannose-binding%20AND%20protein&cat=coreh CFG data]; MBP, also designated mannose-binding lectin, MBL [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Mannose-binding+AND+lectin&maxresults=20 (CFG data)]); and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolin M (Ficolin 1)

2011-03-18T13:01:40Z

Nicole Thielens:

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==
This section documents what is currently known about Ficolin M, its carbohydrate ligand(s), and how they interact to mediate cell communication.
=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Biosynthesis of ligands ===
Pathways for ganglioside biosynthesis have been described ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/geMolecule.jsp GT Database]).
 O-acetylation at positions C-7,8,9 of sialic acid is catalyzed by O-acetyltransferase enzymes associated with the Golgi membrane in mammals<ref>Higa, H.H., Manzi, A. and Varki, A. O-acetylation and de-O-acetylation of sialic acids. Purification, characterization, and properties of a glycosylated rat liver esterase specific for 9-O-acetylated sialic acids. J Biol Chem 264, 19435-19442 (1989)</ref><ref>Butor, C., Higa, H.H. and Varki, A. Structural, immunological, and biosynthetic studies of a sialic acid-specific O-acetylesterase from rat liver. J Biol Chem 268, 10207-10213 (1993)</ref>. Sialic acid O-acetyltransferases have also been identified in bacteria, but they are not homologous to the vertebrate enzymes<ref>Lewis, A.L., Hensler, M.E., Varki, A. and Nizet, V. The group B streptococcal sialic acid O-acetyltransferase is encoded by neuD, a conserved component of bacterial sialic acid biosynthetic gene clusters. J Biol Chem 281, 11186-11192 (2006)</ref>.

=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, and Garred P. Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
Glycan profiling has not been performed.
 

=== Glycogene microarray ===
 

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, and Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palaniyar N, Wallis R, Mollenhauer J, and Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:51:05Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, and Garred P. Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, and Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palaniyar N, Wallis R, Mollenhauer J, and Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:50:36Z

Nicole Thielens: /* Related GBPs */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, and Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palaniyar N, Wallis R, Mollenhauer J, and Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:49:18Z

Nicole Thielens: /* Related GBPs */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palaniyar N, Wallis R, Mollenhauer J, Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:46:14Z

Nicole Thielens: /* Related GBPs */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FIBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palanyar N, Wallis R, Mollenhauer J, Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:44:47Z

Nicole Thielens: /* Related GBPs */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.
 A vertebrate membrane-bound chitin-binding protein, called FIBCD1 (Fibrinogen C domain containing 1) has been identified recently<ref>Schlosser A, Thomsen T, Moeller JB, Nielsen O, Tornoe I, Mollenhauer J, Moestrup SK, Holmskov U. Characterization of FIBCD1 as an acetyl group-binding receptor that binds chitin. J Immunol 183, 3800-3809 (2009)</ref>. The ectodomain of FIBCD1 forms disulfide-linked tetramers assembled from a coiled-coil region, a polycationic region and a C-terminal fibrinogen-related domain. The acetyl-binding site of the fibrinogen-like recognition domain of FBCD1 is homologous to that of TL5A and M-ficolin<ref> Thomsen T, Moeller JB, Schlosser A, Sorensen GL, Moestrup SK, Palanyar N, Wallis R, Mollenhauer J, Holmskov U. The recognition unit of FIBCD1 organizes into a non-covalently linked tetrameric structure and uses a hydrophobic funnel (S1) for acetyl group recognition. J Biol Chem 285, 1229-1028 (2010)</ref>.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T06:08:12Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol 88, 145-158 (2010)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T05:52:24Z

Nicole Thielens: /* Glycogene microarray */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol (2010) Apr 22. (Epub ahead of print)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===
 not performed

=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T05:52:01Z

Nicole Thielens: /* Glycan profiling */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol (2010) Apr 22. (Epub ahead of print)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===
 not performed

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-07-19T05:51:42Z

Nicole Thielens: /* Glycan profiling */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression of GBP and ligands ===
M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.
=== Biosynthesis of ligands ===
 
=== Structure ===

The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol (2010) Apr 22. (Epub ahead of print)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 not performed

=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419 here]), and of 4 variants with the following point mutations in the recognition domain: G221F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421 here]), A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414 here], [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422 here], and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423 here]), G221F/A256V (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415 here]) and Y271F (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417 here]). The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays (click [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708 here] and [http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768 here]).

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T17:18:31Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

 Soluble M-ficolin has been shown to bind to ''Staphylococcus aureus'' through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol (2010) Apr 22. (Epub ahead of print)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417]. The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T17:16:09Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

 Soluble M-ficolin has been shown to bind to "Staphylococcus aureus" through GlcNAc<ref name="Liu 2005"/>. It is tethered to monocytes and granulocytes through binding of its fibrinogen-like recognition domain to sialic acid on the cell surface<ref>Honore C, Rorvig S, Hummelshoj T, Skjoedt MO, Borregaard N, Garred P.Tethering of Ficolin-1 to cell surfaces through recognition of sialic acid by the fibrinogen-like domain. J Leukoc Biol (2010) Apr 22. (Epub ahead of print)</ref>.

== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417]. The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T16:30:32Z

Nicole Thielens: /* Glycan array */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417]. The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T16:29:31Z

Nicole Thielens: /* Cellular expression */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml<ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417].
 The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T16:28:53Z

Nicole Thielens:

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref name="Tanio 2006">Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref name="Garlatti 2007">Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml><ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 The structure of the trimeric fibrinogen-like recognition domain of M-ficolin, alone and in complex with various acetylated ligands, has been solved by X-ray crystallography<ref name="Tanio 2006"/><ref name="Garlatti 2007"/>. A single ligand binding site was observed, located close to the calcium-binding site in the outer part of the trimer and homologous to the GlcNAc binding pocket of the invertebrate tachylectin TL5A <ref>Kairies, N., Beisel, H. G., Fuentes-Prior, P., Tsuda, R., Muta, T., Iwanaga, S., Bode, W., Huber, R., and Kawabata, S. I. Proc. Natl. Acad. Sci. U.S.A. 98, 13519–13524 (2001)</ref>. The essential role of Tyr 271 in the binding specificity for sialic acid was further demonstrated using site-directed mutagenesis<ref name="Gout 35"/>.

=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417].
 The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T15:33:33Z

Nicole Thielens: /* Cellular expression */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref>Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref>Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===
 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml><ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417].
 The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T15:10:43Z

Nicole Thielens: /* Glycan array */

The ficolins are a group of soluble animal proteins with roles in innate immunity<ref>Lu, J. and Le, Y. Ficolins and the fibrinogen-like domain. Immunobiology 199, 190-199 (1998)</ref><ref name="Teh 30">Teh, C., Le, Y., Lee, S. H. and Lu, J. M-ficolin is expressed on monocytes and is a lectin binding to N-acetyl-D-glucosamine and mediates monocyte adhesion and phagocytosis of Escherichia coli. Immunology 101, 225-232 (2000)</ref><ref>Matsushita, M. and Fujita, T. The role of ficolins in innate immunity. Immunobiology 205, 490-497 (2002)</ref><ref name="Endo 32">Endo, Y., Liu, Y. and Fujita, T. Structure and function of ficolins. Adv Exp Med Biol 586, 265-279 (2006) </ref><ref name="Zhang 33">Zhang, X. L. and Ali, M. A. Ficolins: structure, function and associated diseases. Adv Exp Med Biol 632, 105-115 (2008)</ref>. The classification of ficolins as lectins is somewhat controversial since the ligand binding domain in ficolins is specific for acetyl groups in both carbohydrates (e.g. GlcNAc, ManNAc, GalNAc) and non-carbohydrates (eg N-acetylglycine, N-acetylcysteine, acetylcholine)<ref name="Teh 30"/><ref name="Frederiksen 34">Frederiksen, P. D., Thiel, S., Larsen, C. B. and Jensenius, J. C. M-ficolin, an innate immune defence molecule, binds patterns of acetyl groups and activates complement. Scand J Immunol 62, 462-473 (2005)</ref>. Binding of sugars is not primarily dependent on the sugar ring, and sugars that do not contain acetyl groups are generally not ficolin ligands<ref name="Endo 32"/>. However, many of the bacterial surface molecules that appear to be natural ligands for the ficolins contain carbohydrate moieties, and ficolins have similar functional properties to lectins. They are certainly capable of binding acetylated sugars as evidenced by glycan array screening<ref name="Gout 35">Gout, E., Garlatti, V., Smith, D. F., Lacroix, M. M., Dumestre-Perard, C., Lunardi, T., Martin, L., Cesbron, J. Y., Arlaud, G. J., Gaboriaud, C. and Thielens, N. M. Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem (2009) </ref>. Ficolin M (Ficolin 1) and Ficolin L (Ficolin 2) are the most widely studied<ref name="Zhang 33"/><ref name="Frederiksen 34"/><ref name="Gout 35"/><ref name="Liu 2005">Liu, Y., Endo, Y., Iwaki, D., Nakata, M., Matsushita, M., Wada, I., Inoue, K., Munakata, M. and Fujita, T. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol 175, 3150-3156 (2005)</ref><ref>Tanio, M., Kondo, S., Sugio, S. and Kohno, T. Overexpression, purification and preliminary crystallographic analysis of human M-ficolin fibrinogen-like domain. Acta Crystallogr Sect F Struct Biol Cryst Commun 62, 652-655 (2006)</ref><ref>Garlatti, V., Martin, L., Gout, E., Reiser, J. B., Fujita, T., Arlaud, G. J., Thielens, N. M. and Gaboriaud, C. Structural basis for innate immune sensing by M-ficolin and its control by a pH-dependent conformational switch. J Biol Chem 282, 35814-35820 (2007)</ref><ref name="Frankenberger 39">Frankenberger, M., Schwaeble, W. and Ziegler-Heitbrock, L. Expression of M-Ficolin in human monocytes and macrophages. Mol Immunol 45, 1424-1430 (2008)</ref><ref name="Honore 2008">Honore, C., Rorvig, S., Munthe-Fog, L., Hummelshoj, T., Madsen, H. O., Borregaard, N. and Garred, P. The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol 45, 2782-2789 (2008)</ref>. Ficolin L is a serum protein produced in the liver that through association with Mannose-binding protein-associated proteases (MASPs) triggers complement activation in response to binding to pathogen surfaces. It also serves as an opsinin triggering phagocytic uptake of pathogens by neutrophils. Polymorphisms in Ficolin L may have pathophysiological implications<ref>Messias-Reason, I. J., Schafranski, M. D., Kremsner, P. G. and Kun, J. F. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol 157, 395-399 (2009)</ref>. Ficolin M is produced in the lung and has been examined structurally. Ficolin M is found in secretory granules in neutrophils and monocytes, recognizes pathogens, and also activates complement via MASPs<ref name="Frankenberger 39"/>.

See also: paradigm page for [[Ficolins/Mannose-binding protein]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Investigators using CFG resources to study ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 M-ficolin preferentially binds to 9-O-acetylated 2-6-linked sialic acid derivatives and to various glycans containing sialic acid engaged in α 2-3 linkage, including gangliosides<ref name="Gout 35"/>.

=== Cellular expression ===

 M-ficolin has been localized at the surface of blood monocytes and in secretory granules of neutrophils, monocytes, and lung epithelial cells )<ref name="Teh 30"/><ref name="Frederiksen 34"/><ref name="Liu 2005"/>. However, two recent studies have reported its detection in serum, with mean concentrations ranging from 0.06 to 1 μg/ml><ref name="Honore 2008"/><ref>Wittenborn, T., Thiel, S., Jensen, L., Nielsen, H. J., and Jensenius, J. C. Characteristics and biological variations of M-ficolin, a pattern recognition molecule, in plasma. J Innate Immun 2, 167-180 (2010)</ref>.

=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 CFG database search results for ficolin].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The soluble ficolins have been extensively examined using the CFG glycan array ([http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=ficolin&cat=coreh 28 screens]).
 Human M-ficolin
investigators have used CFG glycan arrays to study the ligand binding specificity of human recombinant wild-type M-ficolin at various concentrations[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1602][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2123][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2124][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2412][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2418][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2419], and of 4 variants with the following point mutations in the recognition domain: G221F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2413][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2420][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2421], A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2414][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2422][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2423], G221F/A256V[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2415] and Y271F[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2416][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_2417].
 The binding specificity of the rat homologue of M-ficolin, ficolin B, has also been investigated using CFG glycan arrays[http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1708][http://www.functionalglycomics.org/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_1768].

== Related GBPs ==
This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. Homologs are apparently absent in ''D. melanogaster'' and ''C. elegans''. Several human family members have been described but Ficolin L and M are the best characterized both biochemically and structurally. Ficolin L and H are made in the liver, while Ficolin M and H are produced by the lung. Two ficolins (A and B) are present in mouse. Ficolin B may be the ortholog of Ficolin M.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: John Hanover, Nicole Thielens

Ficolin M (Ficolin 1)

2010-06-15T15:02:45Z

Nicole Thielens:

Ficolin M (Ficolin 1)

2010-06-15T14:54:27Z

Nicole Thielens: /* Cellular expression */

Ficolin M (Ficolin 1)

2010-06-15T14:52:42Z

Nicole Thielens:

Ficolin M (Ficolin 1)

2010-06-15T14:39:28Z

Nicole Thielens:

Ficolin M (Ficolin 1)

2010-06-15T13:29:54Z

Nicole Thielens:

Ficolin M (Ficolin 1)

2010-06-15T13:23:53Z

Nicole Thielens: /* Carbohydrate ligands */

Ficolin M (Ficolin 1)

2010-06-15T13:21:29Z

Nicole Thielens: /* Carbohydrate ligands */

Ficolin M (Ficolin 1)

2010-06-15T13:13:55Z

Nicole Thielens: /* Glycan array */

Ficolins/Mannose-binding protein

2010-06-15T07:03:40Z

Nicole Thielens: /* Glycan array */

Ficolins/Mannose-binding protein

2010-06-15T06:56:12Z

Nicole Thielens: /* Glycan array */

Ficolins/Mannose-binding protein

2010-06-15T06:02:57Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

Ficolins/Mannose-binding protein

2010-06-15T06:00:19Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

Ficolins/Mannose-binding protein

2010-06-15T05:55:46Z

Nicole Thielens: /* Biological roles of GBP-ligand interaction */

Ficolins/Mannose-binding protein

2010-06-15T05:41:01Z

Nicole Thielens: /* Cellular expression */

Ficolins/Mannose-binding protein

2010-06-15T05:08:37Z

Nicole Thielens: /* Cellular expression */

Ficolins/Mannose-binding protein

2010-06-14T17:00:25Z

Nicole Thielens: /* Carbohydrate ligands */

Ficolins/Mannose-binding protein

2010-06-14T16:59:00Z

Nicole Thielens: /* Structure */

Ficolins/Mannose-binding protein

2010-06-14T07:04:04Z

Nicole Thielens: /* References */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins C and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118, 152-6</ref>. H-ficolin does not bind to any of the glycans.

=== Cellular expression ===

 
=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding receptor].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.

== Related GBPs ==
Serum mannose-binding protein (MBP, also designated mannose-binding lectin, MBL) and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2010-06-14T07:03:49Z

Nicole Thielens: /* Carbohydrate ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins C and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622</ref><ref>Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118, 152-6</ref>. H-ficolin does not bind to any of the glycans.

=== Cellular expression ===

 
=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding receptor].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.

== Related GBPs ==
Serum mannose-binding protein (MBP, also designated mannose-binding lectin, MBL) and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>
* Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622.
* Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118, 152-6.

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2010-06-14T07:02:14Z

Nicole Thielens:

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins C and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type<ref>Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622</ref>. H-ficolin does not bind to any of the glycans.

=== Cellular expression ===

 
=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding receptor].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.

== Related GBPs ==
Serum mannose-binding protein (MBP, also designated mannose-binding lectin, MBL) and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>
* Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622.
* Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118, 152-6.

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk

Ficolins/Mannose-binding protein

2010-06-14T06:19:22Z

Nicole Thielens: /* Carbohydrate ligands */

The ficolins share a common organization and function with the collectins: serum mannose-binding and the pulmonary surfactant proteins C and D. All of these proteins are soluble mediators of innate immunity and consist of globular sugar-binding domains attached to collagenous stalks, which can invoke innate immune responses either through complement fixation or interaction with receptors on the surfaces of macrophages. Amongst these proteins, the ficolins have been most extensively investigated with CFG resources, while mannose-binding protein is the best characterized. The ficolins have fibrinogen-like sugar-binding domains, rather than C-type carbohydrate-recognition domains, but conceptually fall within the same group.

See also: paradigm page for [[Ficolin M (Ficolin 1)]]
== CFG Participating Investigators contributing to the understanding of this paradigm ==
Participating Investigators have generated and characterized knockout mice, defined the sugar-binding properties and undertaken structural analysis for members of this glycan-binding protein (GBP) group.
* PIs working on ficolins include: Raymond Dwek, Daniel Mitchell, Nicole Thielens
* PIs investigating other paradigms in this GBP group include: Kurt Drickamer, Ten Feizi, Toshisuke Kawasaki, Laura Kiessling, Reiko Lee, Yuan Lee, Jamie Marth, Kenneth Ng, Michel Nussenzweig, Pauline Rudd, Maureen Taylor, Bill Weis
* Non-PIs with who have used CFG resources to study ficolins include: David Stephens

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===

 L-ficolin preferentially recognizes disulfated LacNAc and tri- and tetrasaccharides containing a terminal LacNAc or GlcNAc unit, provided that the linkage with the following carbohydrate is not of the β1-3 type. H-ficolin does not bind to any of the glycans.

=== Cellular expression ===

 
=== Structure ===

 
=== Biological roles of GBP-ligand interaction ===

 
== CFG resources used in investigations ==
The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ficolin&maxresults=20 ficolin] and [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=mannose-binding&maxresults=20 mannose-binding receptor].

=== Glycan profiling ===

 
=== Glycogene microarray ===

 
=== Knockout mouse lines ===

 
=== Glycan array ===
The binding specificities of several of the ficolins have been analyzed and other members of the group were screened on the CFG glycan array.

== Related GBPs ==
Serum mannose-binding protein (MBP, also designated mannose-binding lectin, MBL) and the pulmonary surfactant proteins SP-C and SP-D

== References ==
<references/>
* Gout E, Garlatti V, Smith DF, Lacroix M M, Dumestre-Perard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM (2010) Carbohydrate recognition properties of human ficolins: Glycan array screening reveals the sialic acid binding specificity of M-ficolin. J Biol Chem 285, 6612-6622.
* Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118, 152-6.

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Kurt Drickamer, Nicole Thielens, Daniel Mitchell, Yvette van Kooyk