Structure of Reovirus σ1 in Complex with Its Receptor Junctional Adhesion Molecule-A

Félix A Rey,Holger M Strauss,Thilo Stehle,Terence S Dermody,Eva Kirchner,Kristen M Guglielmi

doi:10.1371/journal.ppat.1000235

Félix A Rey, Holger M Strauss + Show 4 more

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https://doi.org/10.1371/journal.ppat.1000235

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Journal: PLoS Pathogens	Publication Date: Dec 12, 2008
Citations: 161	License type: CC BY 4.0

Affiliation: Vanderbilt University, University of Tübingen

Abstract

Viral attachment to specific host receptors is the first step in viral infection and serves an essential function in the selection of target cells. Mammalian reoviruses are highly useful experimental models for studies of viral pathogenesis and show promise as vectors for oncolytics and vaccines. Reoviruses engage cells by binding to carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A exists at the cell surface as a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. We report the crystal structure of reovirus attachment protein σ1 in complex with a soluble form of JAM-A. The σ1 protein disrupts the JAM-A dimer, engaging a single JAM-A molecule via virtually the same interface that is used for JAM-A homodimerization. Thus, reovirus takes advantage of the adhesive nature of an immunoglobulin-superfamily receptor by usurping the ligand-binding site of this molecule to attach to the cell surface. The dissociation constant (KD) of the interaction between σ1 and JAM-A is 1,000-fold lower than that of the homophilic interaction between JAM-A molecules, indicating that JAM-A strongly prefers σ1 as a ligand. Analysis of reovirus mutants engineered by plasmid-based reverse genetics revealed residues in σ1 required for binding to JAM-A and infectivity of cultured cells. These studies define biophysical mechanisms of reovirus cell attachment and provide a platform for manipulating reovirus tropism to enhance vector targeting.

Highlights

Viruses have evolved a variety of strategies to engage cellular receptors, often taking advantage of the adhesive properties of these molecules
Mammalian orthoreoviruses are useful models for studies of virus–receptor interactions and viral pathogenesis. They are closely related in structure to adenoviruses and share similar mechanisms of cell attachment and entry
To better understand how viruses engage cellular receptors, we determined the structure of reovirus attachment protein s1 bound to junctional adhesion molecule-A (JAM-A)

Summary

Introduction

Viruses have evolved a variety of strategies to engage cellular receptors, often taking advantage of the adhesive properties of these molecules. Immunoglobulin superfamily (IgSF) members mediate cellular adhesion functions including antigen recognition, stabilization of intercellular junctions, adhesion to extracellular matrices, and leukocyte extravasation [1]. These cell-surface proteins are used as receptors by many viruses [2,3]. Junctional adhesion molecule-A (JAM-A) is an IgSF member that mediates cell-cell contacts and serves as a receptor for mammalian orthoreovirus (reovirus) [4] and feline calicivirus [5]. Reovirus serves as a tractable experimental model for studies of virus-receptor interactions and viral pathogenesis. The recent development of plasmid-based reverse genetics for reovirus offers the opportunity to manipulate these viruses for oncolytic and vaccine applications [7]

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