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J. Biol. Chem., Vol. 281, Issue 31, 21755-21762, August 4, 2006

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Characterization of the HIV N-terminal Fusion Peptide-containing Region in Context of Key gp41 Fusion Conformations^*

From the Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Central to our understanding of human immunodeficiency virus-induced fusion is the high resolution structure of fragments of the gp41 fusion protein folded in a low energy core conformation. However, regions fundamental to fusion, like the fusion peptide (FP), have yet to be characterized in the context of the cognate protein regardless of its conformation. Based on conformation-specific monoclonal antibody recognition, we identified the polar region consecutive to the N36 fragment as a stabilizer of trimeric coiled-coil assembly, thereby enhancing inhibitory potency. This tertiary organization is retained in the context of the hydrophobic FP (N70 fragment). Our data indicate that the N70 fragment recapitulates the expected organization of this region in the viral fusion intermediate (N-terminal half of the pre-hairpin intermediate (N-PHI)), which happens to be the prime target for fusion inhibitors. Regarding the low energy conformation, we show for the first time core formation in the context of the FP (N70 core). The -helical and coiled-coil stabilizing polar region confers substantial thermal stability to the core, whereas the hydrophobic FP does not add further stability. For the two key fusion conformations, N-PHI and N70 core, we find that the FP adopts a nonhelical structure and directs higher order assembly (assembly of coiled coils in N-PHI and assembly of bundles in the N70 core). This supra-molecular organization of coiled coils or folded cores is seen only in the context of the FP. This study is the first to characterize the FP region in the context of the folded core and provides a basic understanding of the role of the elusive FP for key gp41 fusion conformations.

Received for publication, April 3, 2006 , and in revised form, May 31, 2006.

^* This work was supported in part by a grant from the Estate of Julius and Hanna Rosen and by the Israel Science Foundation. 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.

¹ Recipient of the Harold S. and Harriet B. Brady Professorial Chair in Cancer Research. To whom correspondence should be addressed. Tel.: 972-8-934-2711; Fax: 972-8-934-4112; E-mail: yechiel.shai{at}weizmann.ac.il.

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