Ficolins/Mannose-binding protein
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
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[1][2]. 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 [3], and lung surfactant protein D (SP-D) that has been shown to interact with mannoside and glucoside moieties. [4]
Cellular expression
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 [5][6].
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[7]. 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
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 ficolin and 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
- ↑ 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
- ↑ Krarup A, Mitchell DA, Sim RB (2008) Recognition of acetylated oligosaccharides by human L-ficolin. Immunol Lett 118:152-6
- ↑ 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
- ↑ 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.
- ↑ 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
- ↑ 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
- ↑ 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
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
