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J. Biol. Chem., Vol. 278, Issue 48, 48434-48444, November 28, 2003

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Structure-Function Analysis of Reovirus Binding to Junctional Adhesion Molecule 1

IMPLICATIONS FOR THE MECHANISM OF REOVIRUS ATTACHMENT^*

J. Craig Forrest, Jacquelyn A. Campbell, Pierre Schelling¶, Thilo Stehle¶, and Terence S. Dermody||**

From the Departments of Microbiology and Immunology and ^||Pediatrics and Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 and the ^¶Laboratory of Developmental Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

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.

Received for publication, May 30, 2003 , and in revised form, August 26, 2003.

^* This work was supported by Public Health Service awards T32 CA09385 (to J. C. F. and J. A. C.), R01 AI38296 (to T. S. D.), and R01 GM67853 (to T. S. and T. S. D.), the Vanderbilt University Research Council (to J. C. F.), and the Elizabeth B. Lamb Center for Pediatric Research. Additional support was provided by Public Health Service Awards CA68485 (to the Vanderbilt Cancer Center) and DK20593 (to the Vanderbilt Diabetes Research and Training Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Lamb Center for Pediatric Research, D7235 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232. Tel.: 615-343-9943; Fax: 615-343-9723; E-mail: terry.dermody{at}vanderbilt.edu.

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