Koshiba, Takumi and Chan, David C. (2003) The Prefusogenic Intermediate of HIV-1 gp41 Contains Exposed C-peptide Regions. Journal of Biological Chemistry, 278 (9). pp. 7573-7579. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:KOSjbc03
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The human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein is composed of a complex between the surface subunit gp120, which binds to cellular receptors, and the transmembrane subunit gp41. Upon activation of the envelope glycoprotein by cellular receptors, gp41 undergoes conformational changes that mediate fusion of the viral and cellular membranes. Prior to formation of a fusogenic "trimer-of-hairpins" structure, gp41 transiently adopts a prefusogenic conformation whose structural features are poorly understood. An important approach toward understanding structural conformations of gp41 during HIV-1 entry has been to analyze the structural targets of gp41 inhibitors. We have constructed epitope-tagged versions of 5-Helix, a designed protein that binds to the C-peptide region of gp41 and inhibits HIV-1 membrane fusion. Using these 5-Helix variants, we examined which conformation of gp41 is the target of 5-Helix. We find that although 5-Helix binds poorly to native gp41, it binds strongly to gp41 activated by interaction of the envelope protein with either soluble CD4 or membrane-bound cellular receptors. This preferential interaction with activated gp41 results in the accumulation of 5-Helix on the surface of activated cells. These results strongly suggest that the gp41 prefusogenic intermediate is the target of 5-Helix and that this intermediate has a remarkably "open" structure, with exposed C-peptide regions. These results provide important structural information about this intermediate that should facilitate the development of HIV-1 entry inhibitors and may lead to new vaccine strategies.
|Additional Information:||© 2003 The American Society for Biochemistry and Molecular Biology, Inc. Received for publication, October 31, 2002. Published, JBC Papers in Press, December 13, 2002, DOI 10.1074/jbc.M211154200. We gratefully acknowledge Drs. Michael J. Root and Peter S. Kim for providing the p5-Helix and p6-Helix vectors. We also thank Dr. Peter S. Kim for critical reading of the manuscript and members of the Chan lab for helpful comments on the manuscript. This work was supported by National Institutes of Health Grant 7 PO1 GM56552-05 and by a Burroughs Wellcome Fund Career Development Award in Biomedical Sciences.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. [T.K. was a] Postdoctoral fellow of the Japan Society for the Promotion of Science. [D.C.C. was a] Bren Scholar [and a] Rita Allen Scholar.|
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|Deposited On:||04 Oct 2006|
|Last Modified:||04 Nov 2016 19:57|
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