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) and has shown efficacy in clinical trials for aggressive and refractory human tumors (Stoeckel & Hay, 2006; Twigger et al., 2008). Reovirus forms double-shelled particles (Dryden et al., 1993) 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) and mediates viral attachment (Weiner et al., 1980; Lee et al., 1981). 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), 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). 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), 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 (Weis et al.,1998) or the sialic acid-binding domains in the Siglec family of adhesion proteins (Crocker & Varki, 2001), 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

T. S. Dermody and T. Stehle


Progress toward understanding this GBP paradigm

Carbohydrate ligands


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 "reovirus".

Glycan profiling


Glycogene microarray


Knockout mouse lines


Glycan array


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 (Burmeister et al., 2004). 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


Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page:

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