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J. Biol. Chem., Vol. 282, Issue 24, 17930-17940, June 15, 2007

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Reovirus Binding Determinants in Junctional Adhesion Molecule-A^*

Kristen M. Guglielmi, Eva Kirchner^¶, Geoffrey H. Holm^||, Thilo Stehle^¶||, and Terence S. Dermody^||1

From the Departments of Microbiology and Immunology, ^||Pediatrics, and the Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 and the ^¶Interfakultäres Institut für Biochemie, Universität Tübingen, Hoppe-Seyler-Strasse 4, D-72076 Tübingen, Germany

Junctional adhesion molecule-A (JAM-A) serves as a serotype-independent receptor for mammalian orthoreoviruses (reoviruses). The membrane-distal immunoglobulin-like D1 domain of JAM-A is required for homodimerization and binding to reovirus attachment protein 1. We employed a structure-guided mutational analysis of the JAM-A dimer interface to identify determinants of reovirus binding. We purified mutant JAM-A ectodomains for solution-phase and surface plasmon resonance binding studies and expressed mutant forms of full-length JAM-A in Chinese hamster ovary cells to assess reovirus binding and infectivity. Mutation of residues in the JAM-A dimer interface that participate in salt-bridge or hydrogen-bond interactions with apposing JAM-A monomers abolishes the capacity of JAM-A to form dimers. JAM-A mutants incapable of dimer formation form complexes with the 1 head that are indistinguishable from wild-type JAM-A-1 head complexes, indicating that 1 binds to JAM-A monomers. Residues Glu⁶¹ and Lys⁶³ of -strand C and Leu⁷² of -strand C' in the dimer interface are required for efficient JAM-A engagement of strain type 3 Dearing 1. Mutation of neighboring residues alters the kinetics of the 1-JAM-A binding interaction. Prototype reovirus strains type 1 Lang and type 2 Jones share similar, although not identical, binding requirements with type 3 Dearing. These results indicate that reovirus engages JAM-A monomers via residues found mainly on -strands C and C' of the dimer interface and raise the possibility that the distinct disease phenotypes produced in mice following infection with different strains of reovirus are in part attributable to differences in contacts with JAM-A.

Received for publication, March 13, 2007 , and in revised form, April 23, 2007.

^* This work was supported by United States Public Health Service Awards T32 GM08554 (to K. M. G.), R37 AI38296 (to T. S. D.), R01 GM67853 (to T. S. D. and T. S.), and the Elizabeth B. Lamb Center for Pediatric Research. Additional support was provided by the Vanderbilt-Ingram Cancer Center and 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ To whom correspondence should be addressed: Lamb Center for Pediatric Research, D7235 MCN, 1161 21st Ave. S., Nashville, TN 37232-2581. Tel.: 615-343-8911; Fax: 615-343-9723; E-mail: terry.dermody{at}vanderbilt.edu.

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