Structure-function analysis of reovirus binding to junctional adhesion molecule 1. Implications for the mechanism of reovirus attachment.

Forrest JC, Campbell JA, Schelling P, Stehle T, Dermody TS
J Biol Chem. 2003 278 (48): 48434-44

PMID: 12966102 · DOI:10.1074/jbc.M305649200

Mammalian reoviruses are nonenveloped viruses with a long, filamentous attachment protein that dictates disease phenotypes following infection of newborn mice and is a structural homologue of the adenovirus attachment protein. Reoviruses use junctional adhesion molecule 1 (JAM1) as a serotype-independent cellular receptor. JAM1 is a broadly expressed immunoglobulin superfamily protein that forms stable homodimers and regulates tight-junction permeability and lymphocyte trafficking. We employed a series of structure-guided binding and infection experiments to define residues in human JAM1 (hJAM1) important for reovirus-receptor interactions and to gain insight into mechanisms of reovirus attachment. Binding and infection experiments using chimeric and domain deletion mutant receptor molecules indicate that the amino-terminal D1 domain of hJAM1 is required for reovirus attachment, infection, and replication. Reovirus binding to hJAM1 occurs more rapidly than homotypic hJAM1 association and is competed by excess hJAM1 in vitro and on cells. Cross-linking hJAM1 diminishes the capacity of reovirus to bind hJAM1 in vitro and on cells and negates the competitive effects of soluble hJAM1 on reovirus attachment. Finally, mutagenesis studies demonstrate that residues intimately associated with the hJAM1 dimer interface are critical for reovirus interactions with hJAM1. These results suggest that reovirus attachment disrupts hJAM1 dimers and highlight similarities between the attachment strategies of reovirus and adenovirus.

MeSH Terms (27)

Animals Cell Adhesion Molecules Cell Line CHO Cells Cricetinae Cross-Linking Reagents Dimerization Enzyme-Linked Immunosorbent Assay Flow Cytometry Gene Deletion Humans Lymphocytes Mice Models, Molecular Mutagenesis, Site-Directed Phenotype Point Mutation Polymerase Chain Reaction Protein Binding Protein Structure, Tertiary Receptors, Cell Surface Reoviridae Structure-Activity Relationship Tight Junctions Time Factors Transfection Virus Replication

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