Reovirus hemagglutinin (sigma 1)

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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 (Duncan et al., 1978; Coffey et al., 1998)<ref>Duncan, M.R., Stanish, S.M., and Cox, D.C. Differential sensitivity of normal and transformed human  
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'''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 cell 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 name="Rubin1992">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 name="Gentsch1985">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 name="Pacitti1987">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 name="name4">.</ref><ref name="Rubin1992"></ref><ref name="Nibert1995">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 name="Chappell2002">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.
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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  
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pathway. Science 282:1332-1334, 1998.</ref> and has shown efficacy in clinical trials for aggressive and refractory human tumors (Stoeckel & Hay, 2006; Twigger et al., 2008)<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 (Dryden et al., 1993)<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 (Furlong et al., 1988)<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 (Weiner et al., 1980; Lee et al., 1981)<ref></ref><ref></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 (Rubin et al., 1992; Chappell et al., 1997)<ref></ref><ref></ref>, and it functions as a coreceptor on murine L929 (L) cells (Gentsch & Pacitti, 1985; Pacitti & Gentsch, 1987; Paul et al., 1989; Rubin et al., 1992; Nibert et al., 1995)<ref></ref><ref></ref><ref></ref><ref></ref><ref></ref>. Residues involved in sialic acid-binding map to the center of the long fiber, close to the midpoint of the molecule (Chappell et al., 2002)<ref></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.
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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 (Weis et al.,1998)<ref></ref> or the sialic acid-binding domains in the Siglec family of adhesion proteins (Crocker & Varki, 2001)<ref></ref>, 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.
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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 contributing to the understanding of this paradigm ==
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=== Carbohydrate ligands ===
=== Carbohydrate ligands ===
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Reovirus strains of all three serotypes are capable of binding to carbohydrates, which is a property mediated by viral attachment protein sigma 1<ref name="Chappell2000">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 name="Chappell2000">.</ref><ref name="Gentsch1985">.</ref><ref name="name4">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 name="Chappell1997">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 name="Barton2001a">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>.
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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 name="name10">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.
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=== Cellular expression of GBP and ligands ===
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Sialic acid serves as an essential receptor for type 3 reoviruses on murine erythroleukemia (MEL) cells<ref name="Chappell1997">.</ref><ref name="Rubin1992"></ref>. Sialic acid also functions as a coreceptor on murine L929 cells<ref name="Gentsch1985">.</ref><ref name="name4">.</ref><ref name="Rubin1992">.</ref><ref name="Pacitti1987">.</ref><ref name="Nibert1995">.</ref> and human HeLa cells<ref name="Barton2001a">.</ref>. Although not all serotype 3 strains are capable of binding to sialic acid, the majority bind to this carbohydrate.
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Serotype 1 reoviruses are incapable of infecting MEL cells, which support infection only by sialic-acid-binding strains<ref name="Rubin1992">.</ref>. Serotype 1 reoviruses also are insensitive to the growth-inhibitory effects of neuraminidase treatment of L929 cells<ref name="Nibert1995">.</ref>. However, binding of serotype 1 reoviruses to intestinal M cells is diminished by neuraminidase treatment<ref name="name10">.</ref>. The explanation for this discrepancy is not known.
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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 name="Barton2001a">.</ref>, an immunoglobulin superfamily protein engaged by reovirus<ref name="Barton2001b">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 name="Maginnis2006">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 name="Maginnis2008">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 name="Maginnis2006">.</ref><ref name="Maginnis2008">.</ref>.
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=== Biosynthesis of ligands ===
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Serotype 3 reovirus can bind to glycans that terminate with sialic acid in &alpha;2-3, &alpha;2-6, or &alpha;2-8 linkage. Thus, any of the known sialyl transferases ([http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/gtdb.jsp?species=Homo+sapiens&classification=SialylT&linkage_attaching=%3F&linkage_anomeric=%3F&linkage_position=%3F&linkage_base=%3F&pgname=&from=multiple&title=Multiple+Criteria+Search+Results&slideNumber=multipleQuery Human sialyltransferases]) are potentially involved in biosynthesis of target ligands.
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=== Cellular expression ===
 
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=== Structure ===
=== Structure ===
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Structural analysis of the C-terminal half of reovirus attachment protein sigma 1 from strain T3D (residues 246-455) reveals a trimeric structure, in which each monomer is composed of a slender tail and a compact head<ref name="Chappell2002">.</ref>. The C-terminal residues that form the head domain (310-455) consist of two Greek-key motifs that fold into a beta-barrel. The sigma 1 head domain binds to JAM-A<ref name="Barton2001b">.</ref><ref>Kirchner, E., Guglielmi, K.M., Strauss, H.M., Dermody, T.S., and Stehle, T. Structure of reovirus s1 in complex with its receptor junctional adhesion molecule-A. PLoS Path. 4:e1000235, 2008.</ref>. N-terminal residues in the crystallized fragment form a portion of the tail, residues 246-309, which consists of three beta-spiral repeats. Each repeat is composed of two short beta-strands connected by a four-residue beta-turn that has either a proline or a glycine residue at its third position<ref name="Chappell2002">.</ref>. A surface-exposed, variable loop links successive repeats, and trimerization generates an unusual triple beta-spiral motif that also is observed in the adenovirus fiber<ref>van Raaij, M.J., Mitraki, A., Lavigne, G., and Cusack, S. A triple b-spiral in the adenovirus fibre shaft reveals a new structural motif for a fibrous protein. Nature 401:935-938, 1999.</ref>, bacteriophage PRD1 P5 protein<ref>Merckel, M.C., Huiskonen, J.T., Bamford, D.H., Goldman, A., and Tuma, R. The structure of the bacteriophage PRD1 spike sheds light on the evolution of viral capsid architecture. Mol. Cell 18:161-170, 2005.</ref>, and avian reovirus attachment protein sigma C<ref>Guardado, C.P., Fox, G.C., Hermo Parrado, X.L., Llamas-Saiz, A.L., Costas, C., Martinez-Costas, J., Benavente, J., and van Raaij, M.J. Structure of the carboxy-terminal receptor-binding domain of avian reovirus fibre sigmaC. J. Mol. Biol. 354:137-149, 2005.</ref>.
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In addition to the three beta-spiral repeats observed in the crystallized sigma 1 fragment, sequence analysis suggests that residues 167-249 in the T3D sigma 1 tail form an additional five N-terminal beta-spiral repeats<ref name="Chappell2002">.</ref><ref name="Guglielmi2006">Guglielmi, K.M., Johnson, E.M., Stehle, T., and Dermody, T.S. Attachment and cell entry of mammalian orthoreovirus. Curr. Top. Microbiol. Immunol. 309:1-38, 2006.</ref>. Alternatively, these residues may form a combination of beta-spiral repeats and alpha-helical coiled-coil, as suggested by sequence analysis<ref name="Chappell2002">.</ref><ref name="Guglielmi2006">.</ref><ref name="Nibert1990">Nibert, M.L., Dermody, T.S., and Fields, B.N. Structure of the reovirus cell-attachment protein: a model for the domain organization of s1. J. Virol. 64:2976-2989, 1990.</ref> and an observed narrowing in this region in a composite negative-stain electron micrograph<ref>Fraser, R.D.B., Furlong, D.B., Trus, B.L., Nibert, M.L., Fields, B.N., and Steven, A.C. Molecular structure of the cell-attachment protein of reovirus: correlation of computer-processed electron micrographs with sequence-based predictions. J. Virol. 64:2990-3000, 1990.</ref>. The structure of N-terminal residues 1-160 of sigma 1 is unknown. However, a repeating heptad sequence motif is predictive of an amphipathic alpha-helix, which likely assembles into an alpha-helical coiled-coil in the trimer<ref name="Chappell2002">.</ref><ref name="Guglielmi2006">.</ref><ref name="Nibert1990">.</ref>.
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Although the structure of sigma 1 in complex with sialic acid is not yet available, studies using expressed proteins indicate that the region of T3D sigma 1 required for sialic binding resides near the midpoint of the tail, whereas a region just N-terminal to the head domain of T1L sigma 1 binds to carbohydrate<ref name="Chappell2000">.</ref>. In both T1L and T3D sigma 1, interactions with carbohydrate are mediated by a region of predicted beta-spiral<ref name="Chappell2002">.</ref>. Adaptation of non-sialic-acid-binding reoviruses to growth in MEL cells results in amino acid substitutions at residues 198, 202, and 204 of sigma 1 that confer sialic-acid-binding capacity on the resultant viruses<ref name="Chappell1997">.</ref>. Molecular modeling of the sigma 1 tail, based on available structure and sequence data, suggests that these residues are surface-exposed and proximal to one another in the predicted beta-spiral region<ref name="Chappell2002">.</ref>. Thus, residues 198, 202, and 204 are likely to contribute to a sialic-acid-binding site in T3D sigma 1.
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=== Biological roles of GBP-ligand interaction ===
=== Biological roles of GBP-ligand interaction ===
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Sialic acid binding serves an important role in reovirus tropism and pathogenesis in vivo<ref>Barton, E.S., Youree, B.E., Ebert, D.H., Forrest, J.C., Connolly, J.L., Valyi-Nagy, T., Washington, K., Wetzel, J.D., and Dermody, T.S. Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease. J. Clin. Invest. 111:1823-1833, 2003.</ref>. Strain T3SA+, which binds to sialic acid, and strain T3SA-, which does not bind to this carbohydrate, produce equivalent titers in the intestine of newborn mice following peroral inoculation. However, T3SA+ spreads more rapidly from the intestine to sites of secondary replication and produces higher titers in the spleen, liver, and brain. Mice infected with T3SA+, but not T3SA-, develop clinical evidence of bile duct obstruction including jaundice and steatorrhea. Liver tissue from mice infected with T3SA+ show intense inflammation focused at intrahepatic bile ducts, pathology analogous to that found in biliary atresia in human infants, and high levels of T3SA+ antigen in bile duct epithelial cells. T3SA+ binds 100-fold more efficiently than T3SA- to human cholangiocarcinoma cells. Thus, binding to sialic acid targets reovirus to bile duct epithelium and produces a disease reminiscent of infantile biliary atresia.
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== CFG resources used in investigations ==
== 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"].
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 ===
=== Glycan profiling ===
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Not applicable.
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=== Glycogene microarray ===
=== Glycogene microarray ===
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Sigma 1 is not represented on the CFG microarrays, which only contain probes for mouse and human glycogenes.
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=== Knockout mouse lines ===
=== Knockout mouse lines ===
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Not applicable.
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=== Glycan array ===
=== Glycan array ===
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Experiments in progress.  No definitive results have been obtained thus far.
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== Related GBPs ==
== Related GBPs ==
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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 (Burmeister et al., 2004)<ref></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.
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The attachment protein of adenovirus, fiber, is a structural homolog of sigma 1. At least one adenovirus serotype (Ad37; [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=ad37&maxresults=20 CFG data]) 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 78:7727-7736, 2004.</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 ==
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== Acknowledgements ==
== Acknowledgements ==
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The CFG is grateful to the following PIs for their contributions to this wiki page: Mavis McKenna, Thilo Stehle
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The CFG is grateful to the following PIs for their contributions to this wiki page: Terence Dermody, Mavis McKenna, Thilo Stehle.

Current revision as of 17:21, 15 September 2011

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[1][2] and has shown efficacy in clinical trials for aggressive and refractory human tumors[3][4]. Reovirus forms double-shelled particles[5] that contain a segmented dsRNA genome. The reovirus sigma 1 protein is a long, fiber-like molecule that extends from the virion surface[6] and mediates viral attachment[7][8]. The three human serotypes (T1, T2, and T3) differ in cell 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[9], and it functions as a coreceptor on murine L929 (L) cells[10][11][12][9][13]. Residues involved in sialic acid-binding map to the center of the long fiber, close to the midpoint of the molecule[14], 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[15] or the sialic acid-binding domains in the Siglec family of adhesion proteins[16] (see 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.

Contents

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

Reovirus strains of all three serotypes are capable of binding to carbohydrates, which is a property mediated by viral attachment protein sigma 1[17]. 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[17][10][12][18][19]. Hemagglutination by serotype 3 reoviruses is mediated by interactions with alpha-linked sialic acid on several glycosylated erythrocyte proteins such as glycophorin A[20][21]. Reovirus strain T3D binds to sialoglycophorin, but not to asialoglycophorin, with an avidity of ~ 5 x 10e-9 M[22].

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[23]. 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 of GBP and ligands

Sialic acid serves as an essential receptor for type 3 reoviruses on murine erythroleukemia (MEL) cells[19][9]. Sialic acid also functions as a coreceptor on murine L929 cells[10][12][9][11][13] and human HeLa cells[22]. 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[9]. Serotype 1 reoviruses also are insensitive to the growth-inhibitory effects of neuraminidase treatment of L929 cells[13]. However, binding of serotype 1 reoviruses to intestinal M cells is diminished by neuraminidase treatment[23]. 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[22], an immunoglobulin superfamily protein engaged by reovirus[24][25][26]. 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[27] and phage T4[28]. After attachment, reovirus is internalized by receptor-mediated endocytosis[29][30][31][32][33][34] using a mechanism dependent on beta 1 integrin[32][34].

Biosynthesis of ligands

Serotype 3 reovirus can bind to glycans that terminate with sialic acid in α2-3, α2-6, or α2-8 linkage. Thus, any of the known sialyl transferases (Human sialyltransferases) are potentially involved in biosynthesis of target ligands.

Structure

Structural analysis of the C-terminal half of reovirus attachment protein sigma 1 from strain T3D (residues 246-455) reveals a trimeric structure, in which each monomer is composed of a slender tail and a compact head[14]. The C-terminal residues that form the head domain (310-455) consist of two Greek-key motifs that fold into a beta-barrel. The sigma 1 head domain binds to JAM-A[24][35]. N-terminal residues in the crystallized fragment form a portion of the tail, residues 246-309, which consists of three beta-spiral repeats. Each repeat is composed of two short beta-strands connected by a four-residue beta-turn that has either a proline or a glycine residue at its third position[14]. A surface-exposed, variable loop links successive repeats, and trimerization generates an unusual triple beta-spiral motif that also is observed in the adenovirus fiber[36], bacteriophage PRD1 P5 protein[37], and avian reovirus attachment protein sigma C[38].

In addition to the three beta-spiral repeats observed in the crystallized sigma 1 fragment, sequence analysis suggests that residues 167-249 in the T3D sigma 1 tail form an additional five N-terminal beta-spiral repeats[14][39]. Alternatively, these residues may form a combination of beta-spiral repeats and alpha-helical coiled-coil, as suggested by sequence analysis[14][39][40] and an observed narrowing in this region in a composite negative-stain electron micrograph[41]. The structure of N-terminal residues 1-160 of sigma 1 is unknown. However, a repeating heptad sequence motif is predictive of an amphipathic alpha-helix, which likely assembles into an alpha-helical coiled-coil in the trimer[14][39][40].

Although the structure of sigma 1 in complex with sialic acid is not yet available, studies using expressed proteins indicate that the region of T3D sigma 1 required for sialic binding resides near the midpoint of the tail, whereas a region just N-terminal to the head domain of T1L sigma 1 binds to carbohydrate[17]. In both T1L and T3D sigma 1, interactions with carbohydrate are mediated by a region of predicted beta-spiral[14]. Adaptation of non-sialic-acid-binding reoviruses to growth in MEL cells results in amino acid substitutions at residues 198, 202, and 204 of sigma 1 that confer sialic-acid-binding capacity on the resultant viruses[19]. Molecular modeling of the sigma 1 tail, based on available structure and sequence data, suggests that these residues are surface-exposed and proximal to one another in the predicted beta-spiral region[14]. Thus, residues 198, 202, and 204 are likely to contribute to a sialic-acid-binding site in T3D sigma 1.

Biological roles of GBP-ligand interaction

Sialic acid binding serves an important role in reovirus tropism and pathogenesis in vivo[42]. Strain T3SA+, which binds to sialic acid, and strain T3SA-, which does not bind to this carbohydrate, produce equivalent titers in the intestine of newborn mice following peroral inoculation. However, T3SA+ spreads more rapidly from the intestine to sites of secondary replication and produces higher titers in the spleen, liver, and brain. Mice infected with T3SA+, but not T3SA-, develop clinical evidence of bile duct obstruction including jaundice and steatorrhea. Liver tissue from mice infected with T3SA+ show intense inflammation focused at intrahepatic bile ducts, pathology analogous to that found in biliary atresia in human infants, and high levels of T3SA+ antigen in bile duct epithelial cells. T3SA+ binds 100-fold more efficiently than T3SA- to human cholangiocarcinoma cells. Thus, binding to sialic acid targets reovirus to bile duct epithelium and produces a disease reminiscent of infantile biliary atresia.

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 "reovirus".

Glycan profiling

Not applicable.

Glycogene microarray

Sigma 1 is not represented on the CFG microarrays, which only contain probes for mouse and human glycogenes.

Knockout mouse lines

Not applicable.

Glycan array

Experiments in progress. No definitive results have been obtained thus far.

Related GBPs

The attachment protein of adenovirus, fiber, is a structural homolog of sigma 1. At least one adenovirus serotype (Ad37; CFG data) is known to bind glycan receptors via residues in the fiber protein[43]. 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.

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Acknowledgements

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

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