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

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 (K D ) 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. Mammalian orthoreoviruses (reoviruses) 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. The receptor for reovirus, junctional adhesion molecule-A (JAM-A), is a component of cellular junctions and also used as a receptor by feline calicivirus. To better understand how viruses engage cellular receptors, we determined the structure of reovirus attachment protein σ1 bound to JAM-A. The structure provides an understanding of the biological function of the interaction and yields information that may enable targeting of reovirus to alternate receptors. Since the repertoire of receptors bound by a virus contributes importantly to determining which types of cells are infected, such targeting plays an essential role in gene delivery for vaccine or therapeutic applications. New cancer therapy approaches include the use