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

PLoS Pathogens

Thilo Stehle¹  Kristen M. Guglielmi¹  Holger M. Strauss²  Eva Kirchner³  Terence S. Dermody⁴ 

[1] Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America;Interfaculty Institute for Biochemistry, University of Tuebingen, Tuebingen, Germany;Nanolytics Gesellschaft für Kolloidanalytik mbH, Potsdam, Germany

关键词: Dimers (Chemical physics);    Crystal structure;    Adenoviruses;    Sedimentation;    Reoviruses;    Viral structure;    HeLa cells;    Cell binding;   

DOI  :  10.1371/journal.ppat.1000235

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY