Reovirus hemagglutinin (sigma 1)

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=== Glycan profiling ===
=== Glycan profiling ===
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Not performed.
+
Not applicable.
=== Glycogene microarray ===
=== Glycogene microarray ===

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.

References

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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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