View source for Reovirus hemagglutinin (sigma 1)

'''Mammalian orthoreoviruses (reoviruses)''' are useful models for studies of viral receptor recognition and the pathogenesis of viral disease. Reovirus also efficiently lyses tumor cells in experimental animals<ref>Duncan, M.R., Stanish, S.M., and Cox, D.C. Differential sensitivity of normal and transformed human cells to reovirus infection. J. Virol. 28:444-449, 1978.</ref><ref> Coffey, M.C., Strong, J.E., Forsyth, P.A., and Lee, P.W. Reovirus therapy of tumors with activated Ras pathway. Science 282:1332-1334, 1998.</ref> and has shown efficacy in clinical trials for aggressive and refractory human tumors<ref>Stoeckel, J., and Hay, J.G. Drug evaluation: Reolysin--wild-type reovirus as a cancer therapeutic. Curr. Opin. Mol. Ther. 8:249-260, 2006.</ref><ref>Twigger, K., Vidal, L., White, C.L., De Bono, J.S., Bhide, S., Coffey, M., Thompson, B., Vile, R.G., Heinemann, L., Pandha, H.S., et al. Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy. Clin. Cancer Res. 14:912-923, 2008. </ref>. Reovirus forms double-shelled particles<ref>Dryden, K.A., Wang, G., Yeager, M., Nibert, M.L., Coombs, K.M., Furlong, D.B., Fields, B.N., and Baker, T.S. Early steps in reovirus infection are associated with dramatic changes in supramolecular structure and protein conformation: analysis of virions and subviral particles by cryoelectron microscopy and image reconstruction. J. Cell Biol. 122:1023-1041, 1993.</ref> that contain a segmented dsRNA genome. The reovirus sigma 1 protein is a long, fiber-like molecule that extends from the virion surface<ref>Furlong, D.B., Nibert, M.L., and Fields, B.N. Sigma 1 protein of mammalian reoviruses extends from the surfaces of viral particles. J. Virol. 62:246-256, 1988.</ref> and mediates viral attachment<ref>Weiner, H.L., Ault, K.A., and Fields, B.N. Interaction of reovirus with cell surface receptors. I. Murine and human lymphocytes have a receptor for the hemagglutinin of reovirus type 3. J. Immunol. 124:2143-2148, 1980.</ref><ref>Lee, P.W.K., Hayes, E.C., and Joklik, W.K. Protein σ1 is the reovirus cell attachment protein. Virology 108:156-163, 1981.</ref>. The three human serotypes (T1, T2, and T3) differ in cellular tropism, which correlates directly with receptor-binding properties of sigma 1. Sialic acid serves as an essential receptor for T3 reovirus on murine erythroleukemia (MEL) cells<ref>Rubin, D.H., Wetzel, J.D., Williams, W.V., Cohen, J.A., Dworkin, C., and Dermody, T.S. Binding of type 3 reovirus by a domain of the σ1 protein important for hemagglutination leads to infection of murine erythroleukemia cells. J. Clin. Invest. 90:2536-2542, 1992.</ref>, and it functions as a coreceptor on murine L929 (L) cells<ref>Gentsch, J.R., and Pacitti, A.F. Effect of neuraminidase treatment of cells and effect of soluble glycoproteins on type 3 reovirus attachment to murine L cells. J. Virol. 56:356-364, 1985.</ref><ref>Pacitti, A., and Gentsch, J.R. Inhibition of reovirus type 3 binding to host cells by sialylated glycoproteins is mediated through the viral attachment protein. J. Virol. 61:1407-1415, 1987. </ref><ref>Paul, R.W., Choi, A.H., and Lee, P.W.K. The α-anomeric form of sialic acid is the minimal receptor determinant recognized by reovirus. Virology 172:382-385, 1989.</ref><ref>Rubin, D.H., Wetzel, J.D., Williams, W.V., Cohen, J.A., Dworkin, C., and Dermody, T.S. Binding of type 3 reovirus by a domain of the σ1 protein important for hemagglutimurine erythroleukemia cells. J. Clin. Invest. 90:2536-2542, 1992.</ref><ref>Nibert, M.L., Chappell, J.D., and Dermody, T.S. Infectious subvirion particles of reovirus type 3 Dearing exhibit a loss in infectivity and contain a cleaved σ1 protein. J. Virol. 69:5057-5067, 1995.</ref>. Residues involved in sialic acid-binding map to the center of the long fiber, close to the midpoint of the molecule<ref>Chappell, J.D., Prota, A., Dermody, T.S., and Stehle, T. Crystal structure of reovirus attachment protein σ1 reveals evolutionary relationship to adenovirus fiber. EMBO J. 21:1-11, 2002.</ref>, in a repetitive structural region known as the triple β-spiral. The T1 sigma 1 protein binds to cell-surface glycans of unknown structure.


The triple β-spiral of '''sigma 1''' functions as a trimerization domain and defines a novel carbohydrate-recognition motif. Other carbohydrate-recognition domains, such as those of the C-type lectin superfamily<ref>Weis, W.I., Taylor, M.E., and Drickamer, K. The C-type lectin superfamily in the immune system. Immunol. Rev. 163:19-34, 1998.</ref> or the sialic acid-binding domains in the Siglec family of adhesion proteins<ref>Crocker, P.R., and Varki, A. Siglecs in the immune system. Immunology 103:137-145, 2001.</ref>(see [http://glycobank.mit.edu/glycoWiki/Main_Page Siglec paradigms]), have been described, but none are formed by a repetitive, fiber-like structure such as the one present in sigma 1. In fact, the domain in sigma 1 that binds sialic acid constitutes a carbohydrate-binding “cassette” that could be endowed with altered ligand-binding properties or grafted onto other trimeric structures and used to create avidity for carbohydrates. For example, the adenovirus fiber shaft could be licensed with sialic acid-binding capacity using this approach. These properties render the sigma 1 protein unique among the structurally known glycan-binding moieties.

== CFG Participating Investigators contributing to the understanding of this paradigm ==
CFG Participating Investigators (PIs) contributing to the understanding of sigma 1 include: Terence Dermody, Thilo Stehle

== Progress toward understanding this GBP paradigm ==

=== Carbohydrate ligands ===
<br>Reovirus strains of all three serotypes are capable of binding to carbohydrates, which is a property mediated by viral attachment protein sigma 1<ref>Chappell, J.D., Duong, J.L., Wright, B.W., and Dermody, T.S. Identification of carbohydrate-binding domains in the attachment proteins of type 1 and type 3 reoviruses. J. Virol. 74:8472-8479, 2000.</ref>. Substantial evidence indicates that serotype 3 reoviruses bind to sialic acid, whereas the identity of carbohydrates bound by serotype 1 and 2 reoviruses is less clear. Serotype 3 reoviruses bind to alpha-linked sialic acid in either alpha2,3 or alpha2,6 linkages on a variety of cell types<ref>Chappell, J.D., Duong, J.L., Wright, B.W., and Dermody, T.S. Identification of carbohydrate-binding domains in the attachment proteins of type 1 and type 3 reoviruses. J. Virol. 74:8472-8479, 2000.</ref><ref>Gentsch, J.R., and Pacitti, A.F. Effect of neuraminidase treatment of cells and effect of soluble glycoproteins on type 3 reovirus attachment to murine L cells. J. Virol. 56:356-364, 1985.</ref><ref>Paul, R.W., Choi, A.H., and Lee, P.W.K. The a-anomeric form of sialic acid is the minimal receptor determinant recognized by reovirus. Virology 172:382-385, 1989.</ref><ref>Dermody, T.S., Nibert, M.L., Bassel-Duby, R., and Fields, B.N. Sequence diversity in S1 genes and S1 translation products of 11 serotype 3 reovirus strains. J. Virol. 64:4842-4850, 1990.</ref><ref>Chappell, J.D., Gunn, V.L., Wetzel, J.D., Baer, G.S., and Dermody, T.S. Mutations in type 3 reovirus that determine binding to sialic acid are contained in the fibrous tail domain of viral attachment protein s1. J. Virol. 71:1834-1841, 1997.</ref>. Hemagglutination by serotype 3 reoviruses is mediated by interactions with alpha-linked sialic acid on several glycosylated erythrocyte proteins such as glycophorin A<ref>Gentsch, J.R., and Pacitti, A.F. Differential interaction of reovirus type 3 with sialylated receptor components on animal cells. Virology 161:245-248, 1987.</ref><ref>Paul, R.W., and Lee, P.W.K. Glycophorin is the reovirus receptor on human erythrocytes. Virology 159:94-101, 1987.</ref>. Reovirus strain T3D binds to sialoglycophorin, but not to asialoglycophorin, with an avidity of ~ 5 x 10e-9 M<ref>Barton, E.S., Connolly, J.L., Forrest, J.C., Chappell, J.D., and Dermody, T.S. Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening. J. Biol. Chem. 276:2200-2211, 2001.</ref>.

Serotype 1 reoviruses also appear to bind to sialic acid in some contexts. Reovirus strain T1L, but not strain T3D, binds to the apical surface of microfold (M) cells, but not to enterocytes, in tissue sections of rabbit Peyer’s patches<ref>Helander, A., Silvey, K.J., Mantis, N.J., Hutchings, A.B., Chandran, K., Lucas, W.T., Nibert, M.L., and Neutra, M.R. The viral s1 protein and glycoconjugates containing a2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces. J. Virol. 77:7964-7977, 2003.</ref>. Binding is inhibited by pre-incubation of the tissue sections with neuraminidase or with lectins that specifically recognize alpha2-3-linked sialic acid.

=== Cellular expression ===
<br>Sialic acid serves as an essential receptor for type 3 reoviruses on murine erythroleukemia (MEL) cells<ref>Chappell, J.D., Gunn, V.L., Wetzel, J.D., Baer, G.S., and Dermody, T.S. Mutations in type 3 reovirus that determine binding to sialic acid are contained in the fibrous tail domain of viral attachment protein s1. J. Virol. 71:1834-1841, 1997.</ref><ref>Rubin, D.H., Wetzel, J.D., Williams, W.V., Cohen, J.A., Dworkin, C., and Dermody, T.S. Binding of type 3 reovirus by a domain of the s1 protein important for hemagglutination leads to infection of murine erythroleukemia cells. J. Clin. Invest. 90:2536-2542, 1992.</ref>. Sialic acid also functions as a coreceptor on murine L929 cells<ref>Gentsch, J.R., and Pacitti, A.F. Effect of neuraminidase treatment of cells and effect of soluble glycoproteins on type 3 reovirus attachment to murine L cells. J. Virol. 56:356-364, 1985.</ref><ref>Paul, R.W., Choi, A.H., and Lee, P.W.K. The a-anomeric form of sialic acid is the minimal receptor determinant recognized by reovirus. Virology 172:382-385, 1989.</ref><ref>Rubin, D.H., Wetzel, J.D., Williams, W.V., Cohen, J.A., Dworkin, C., and Dermody, T.S. Binding of type 3 reovirus by a domain of the s1 protein important for hemagglutination leads to infection of murine erythroleukemia cells. J. Clin. Invest. 90:2536-2542, 1992.</ref><ref>Pacitti, A., and Gentsch, J.R. Inhibition of reovirus type 3 binding to host cells by sialylated glycoproteins is mediated through the viral attachment protein. J. Virol. 61:1407-1415, 1987.</ref><ref>Nibert, M.L., Chappell, J.D., and Dermody, T.S. Infectious subvirion particles of reovirus type 3 Dearing exhibit a loss in infectivity and contain a cleaved s1 protein. J. Virol. 69:5057-5067, 1995.</ref> and human HeLa cells<ref>Barton, E.S., Connolly, J.L., Forrest, J.C., Chappell, J.D., and Dermody, T.S. Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening. J. Biol. Chem. 276:2200-2211, 2001.</ref>. Although not all serotype 3 strains are capable of binding to sialic acid, the majority bind to this carbohydrate.

Serotype 1 reoviruses are incapable of infecting MEL cells, which support infection only by sialic-acid-binding strains<ref>Rubin, D.H., Wetzel, J.D., Williams, W.V., Cohen, J.A., Dworkin, C., and Dermody, T.S. Binding of type 3 reovirus by a domain of the s1 protein important for hemagglutination leads to infection of murine erythroleukemia cells. J. Clin. Invest. 90:2536-2542, 1992.</ref>. Serotype 1 reoviruses also are insensitive to the growth-inhibitory effects of neuraminidase treatment of L929 cells<ref>Nibert, M.L., Chappell, J.D., and Dermody, T.S. Infectious subvirion particles of reovirus type 3 Dearing exhibit a loss in infectivity and contain a cleaved s1 protein. J. Virol. 69:5057-5067, 1995.</ref>. However, binding of serotype 1 reoviruses to intestinal M cells is diminished by neuraminidase treatment<ref>Helander, A., Silvey, K.J., Mantis, N.J., Hutchings, A.B., Chandran, K., Lucas, W.T., Nibert, M.L., and Neutra, M.R. The viral s1 protein and glycoconjugates containing a2-3-linked sialic acid are involved in type 1 reovirus adherence to M cell apical surfaces. J. Virol. 77:7964-7977, 2003.</ref>. The explanation for this discrepancy is not known.

Reovirus employs a multi-step mechanism of viral attachment in which a low-affinity interaction with sialic acid serves to tether the virion to target cells and precedes a high-affinity interaction with JAM-A<ref>arton, E.S., Connolly, J.L., Forrest, J.C., Chappell, J.D., and Dermody, T.S. Utilization of sialic acid as a coreceptor enhances reovirus attachment by multistep adhesion strengthening. J. Biol. Chem. 276:2200-2211, 2001.</ref>, an immunoglobulin superfamily protein engaged by reovirus<ref>Barton, E.S., Forrest, J.C., Connolly, J.L., Chappell, J.D., Liu, Y., Schnell, F., Nusrat, A., Parkos, C.A., and Dermody, T.S. Junction adhesion molecule is a receptor for reovirus. Cell 104:441-451, 2001.</ref><ref>Prota, A.E., Campbell, J.A., Schelling, P., Forrest, J.C., Peters, T.R., Watson, M.J., Aurrand-Lions, M., Imhof, B., Dermody, T.S., and Stehle, T. Crystal structure of human junctional adhesion molecule 1: implications for reovirus binding. Proc. Natl. Acad. Sci. U. S. A. 100:5366-5371, 2003.</ref><ref>Campbell, J.A., Shelling, P., Wetzel, J.D., Johnson, E.M., Wilson, G.A.R., Forrest, J.C., Aurrand-Lions, M., Imhof, B., Stehle, T., and Dermody, T.S. Junctional adhesion molecule-A serves as a receptor for prototype and field-isolate strains of mammalian reovirus. J. Virol. 79:7967-7978, 2005.</ref>. By virtue of its rapid association rate, virus binding to sialic acid adheres the virion to the cell surface, thereby enabling it to diffuse laterally until it encounters JAM-A. Such lateral diffusion has been reported for influenza virus<ref>Sagik, B., Puck, T., and Levine, S. Quantitative aspects of the spontaneous elution of influenza virus from red cells. J. Exp. Med. 99:251-260, 1954.</ref> and phage T4<ref>Wilson, J.H., Luftig, R.B., and Wood, W.B. Interaction of bacteriophage T4 tail fiber components with a lipopolysaccharide fraction from Escherichia coli. J. Mol. Biol. 51:423-434, 1970.</ref>. After attachment, reovirus is internalized by receptor-mediated endocytosis<ref>Borsa, J., Morash, B.D., Sargent, M.D., Copps, T.P., Lievaart, P.A., and Szekely, J.G. Two modes of entry of reovirus particles into L cells. J. Gen. Virol. 45:161-170, 1979.</ref><ref>Borsa, J., Sargent, M.D., Lievaart, P.A., and Copps, T.P. Reovirus: evidence for a second step in the intracellular uncoating and transcriptase activation process. Virology 111:191-200, 1981.</ref><ref>Ehrlich, M., Boll, W., Van Oijen, A., Hariharan, R., Chandran, K., Nibert, M.L., and Kirchhausen, T. Endocytosis by random initiation and stabilization of clathrin-coated pits. Cell 118:591-605, 2004.</ref><ref>Maginnis, M.S., Forrest, J.C., Kopecky-Bromberg, S.A., Dickeson, S.K., Santoro, S.A., Zutter, M.M., Nemerow, G.R., Bergelson, J.M., and Dermody, T.S. b1 integrin mediates internalization of mammalian reovirus. J. Virol. 80:2760-2770, 2006.</ref><ref>Sturzenbecker, L.J., Nibert, M.L., Furlong, D.B., and Fields, B.N. Intracellular digestion of reovirus particles requires a low pH and is an essential step in the viral infectious cycle. J. Virol. 61:2351-2361, 1987.</ref><ref>Maginnis, M.S., Mainou, B.A., Derdowski, A.M., Johnson, E.M., Zent, R., and Dermody, T.S. NPXY motifs in the b1 integrin cytoplasmic tail are required for functional reovirus entry. J. Virol. 82:3181-3191, 2008.</ref> using a mechanism dependent on beta 1 integrin<ref>Maginnis, M.S., Forrest, J.C., Kopecky-Bromberg, S.A., Dickeson, S.K., Santoro, S.A., Zutter, M.M., Nemerow, G.R., Bergelson, J.M., and Dermody, T.S. b1 integrin mediates internalization of mammalian reovirus. J. Virol. 80:2760-2770, 2006.</ref><ref>Maginnis, M.S., Mainou, B.A., Derdowski, A.M., Johnson, E.M., Zent, R., and Dermody, T.S. NPXY motifs in the b1 integrin cytoplasmic tail are required for functional reovirus entry. J. Virol. 82:3181-3191, 2008.</ref>.

=== Structure ===

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

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== 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=reovirus&maxresults=20 CFG database search results for "reovirus"].

=== Glycan profiling ===

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=== Glycogene microarray ===

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=== Knockout mouse lines ===

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=== Glycan array ===

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== Related GBPs ==
The attachment protein of adenovirus, fiber, is a structural homolog of sigma 1. At least one adenovirus serotype (Ad37) is known to bind glycan receptors via residues in the fiber protein<ref>Burmeister WP, Guilligay D, Cusack S, Wadell G, Arnberg N: Crystal structure of species D adenovirus fiber knobs and their sialic acid binding sites. Journal of Virology 2004, 78:7727-7736.</ref>. The actual binding site is not homologous. However, information about reovirus glycan binding could also be used to engineer adenovirus fiber proteins (or other trimeric fiber-like proteins) that possess novel glycan-binding properties.

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Terence Dermody, Mavis McKenna, Thilo Stehle.