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J. Biol. Chem., Vol. 283, Issue 10, 6418-6427, March 7, 2008

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Molecular Architecture of the Bipartite Fusion Loops of Vesicular Stomatitis Virus Glycoprotein G, a Class III Viral Fusion Protein^*

Xiangjie Sun, Sandrine Belouzard, and Gary R. Whittaker¹

From the Department of Microbiology and Immunology, College of Veterinary Medicine, and Graduate Program in Microbiology, Cornell University, Ithaca, New York 14853

The glycoprotein of vesicular stomatitis virus (VSV G) mediates fusion of the viral envelope with the host cell, with the conformational changes that mediate VSV G fusion activation occurring in a reversible, low pH-dependent manner. Based on its novel structure, VSV G has been classified as class III viral fusion protein, having a predicted bipartite fusion domain comprising residues Trp-72, Tyr-73, Tyr-116, and Ala-117 that interacts with the host cell membrane to initiate the fusion reaction. Here, we carried out a systematic mutagenesis study of the predicted VSV G fusion loops, to investigate the functional role of the fusion domain. Using assays of low pH-induced cell-cell fusion and infection studies of mutant VSV G incorporated into viral particles, we show a fundamental role for the bipartite fusion domain. We show that Trp-72 is a critical residue for VSV G-mediated membrane fusion. Trp-72 could only tolerate mutation to a phenylalanine residue, which allowed only limited fusion. Tyr-73 and Tyr-116 could be mutated to other aromatic residues without major effect but could not tolerate any other substitution. Ala-117 was a less critical residue, with only charged residues unable to allow fusion activation. These data represent a functional analysis of predicted bipartite fusion loops of VSV G, a founder member of the class III family of viral fusion proteins.

Received for publication, October 31, 2007 , and in revised form, December 22, 2007.

^* This work was supported by the Cornell University Nanobiotechnology Center a Science and Technology Center program of the National Science Foundation under agreement number ECS-987677, and NIAID, National Institutes of Health. 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 S1 and S2.

¹ To whom correspondence should be addressed: C4127 VMC, Dept. Microbiology & Immunology, Cornell University, Ithaca NY 14853. Tel.: 607-253-4019; Fax: 607-253-3385; E-mail: grw7{at}cornell.edu.

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