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Journal of Virology, June 2005, p. 7503-7513, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7503-7513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Localization of Regions in CD46 That Interact with Adenovirus

Anuj Gaggar,2 Dmitry M. Shayakhmetov,1 M. Kathryn Liszewski,3 John P. Atkinson,3 and André Lieber1,2*

Department of Medicine,1 Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195,2 Department of Rheumatology, Washington University School of Medicine, St. Louis, Missouri3

Received 17 May 2004/ Accepted 28 February 2005

A variety of pathogens use CD46, a ubiquitously expressed membrane protein that regulates complement activation, as a cellular attachment receptor. While the CD46 binding sites of several pathogens, including measles virus, Neisseria gonorrhea, and human herpesvirus 6, have been described, the region of CD46 responsible for adenovirus binding has not been determined. In this study, we used competition experiments with known CD46 ligands, CD46-specific antibodies, and a set of CD46 mutants to localize the binding domain for the group B adenovirus serotype 35 (Ad35). Our results show that Ad35 competes with measles virus for binding to CD46 but not with complement protein C3b. We further show that this interaction is a protein-protein interaction and that N glycosylations do not critically contribute to infection with Ad35 fiber-containing Ad vectors. Our data demonstrate that the native conformation of the CCP2 domain is crucial for Ad35 binding and that the substitution of amino acids at positions 130 to 135 or 152 to 156 completely abolishes the receptor function of CD46. These regions localize to the same planar face of CD46 and likely form an extended adenovirus binding surface, since no single amino acid substitution within these areas eliminates virus binding. Finally, we demonstrate that the infection with a virus possessing human group B serotype Ad11 fibers is also mediated by the CCP2 domain. This information is important to better characterize the mechanisms of the receptor recognition by adenovirus relative to other pathogens that interact with CD46, and it may help in the design of antiviral therapeutics against adenovirus serotypes that use CD46 as a primary cellular attachment receptor.

* Corresponding author. Mailing address: University of Washington School of Medicine, Division of Medical Genetics, Box 357720, Seattle, WA 98195. Phone: (206) 221-3973. Fax: (206) 685-8675. E-mail: lieber00{at}u.washington.edu.

Journal of Virology, June 2005, p. 7503-7513, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7503-7513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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