Suntoke, Tara R. and Chan, David C. (2005) The Fusion Activity of HIV-1 gp41 Depends on Interhelical Interactions. Journal of Biological Chemistry, 280 (20). pp. 19852-19857. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:SUNjbc05
- Published Version
See Usage Policy.
Use this Persistent URL to link to this item: http://resolver.caltech.edu/CaltechAUTHORS:SUNjbc05
Infection by human immunodeficiency virus type I requires the fusogenic activity of gp41, the transmembrane subunit of the viral envelope protein. Crystallographic studies have revealed that fusion-active gp41 is a "trimer-of-hairpins" in which three central N-terminal helices form a trimeric coiled coil surrounded by three antiparallel C-terminal helices. This structure is stabilized primarily by hydrophobic, interhelical interactions, and several critical contacts are made between residues that form a deep cavity in the N-terminal trimer and the C-helix residues that pack into this cavity. In addition, the trimer-of-hairpins structure has an extensive network of hydrogen bonds within a conserved glutamine-rich layer of poorly understood function. Formation of the trimer-of-hairpins structure is thought to directly force the viral and target membranes together, resulting in membrane fusion and viral entry. We test this hypothesis by constructing four series of gp41 mutants with disrupted interactions between the N- and C-helices. Notably, in the three series containing mutations within the cavity, gp41 activity correlates well with the stability of the N-C interhelical interaction. In contrast, a fourth series of mutants involving the glutamine layer residue Gln-653 show fusion defects even though the stability of the hairpin is close to wild-type. These results provide evidence that gp41 hairpin stability is critical for mediating fusion and suggest a novel role for the glutamine layer in gp41 function.
|Additional Information:||© 2005 the American Society for Biochemistry and Molecular Biology. Received for publication, February 25, 2005. Originally published In Press as doi:10.1074/jbc.M502196200 on March 16, 2005. We thank Drs. R. Olsen and A. Herr for assistance with the sedimentation equilibrium experiments, Dr. J. Kaiser for help with Fig. 1C, Drs. D. Eckert and M. Kay for critical review of the manuscript, and E. Griffin and members of the Chan lab for helpful discussions. This work was supported in part by National Institutes of Health Grant PO1 GM56552. 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. Supported by the Massachusetts Institute of Technology and Merck Pharmaceuticals.|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Archive Administrator|
|Deposited On:||26 Dec 2006|
|Last Modified:||04 Nov 2016 17:28|
Repository Staff Only: item control page