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Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion

Many viral fusion proteins exhibit a six-helix bundle as a core structure. HIV Env–induced fusion was studied to resolve whether membrane merger was due to the transition into the bundle configuration or occurred after bundle formation. Suboptimal temperature was used to arrest fusion at an intermed...

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Autores principales: Melikyan, Grigory B., Markosyan, Ruben M., Hemmati, Hila, Delmedico, Mary K., Lambert, Dennis M., Cohen, Fredric S.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2000
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192659/
https://www.ncbi.nlm.nih.gov/pubmed/11038187
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author Melikyan, Grigory B.
Markosyan, Ruben M.
Hemmati, Hila
Delmedico, Mary K.
Lambert, Dennis M.
Cohen, Fredric S.
author_facet Melikyan, Grigory B.
Markosyan, Ruben M.
Hemmati, Hila
Delmedico, Mary K.
Lambert, Dennis M.
Cohen, Fredric S.
author_sort Melikyan, Grigory B.
collection PubMed
description Many viral fusion proteins exhibit a six-helix bundle as a core structure. HIV Env–induced fusion was studied to resolve whether membrane merger was due to the transition into the bundle configuration or occurred after bundle formation. Suboptimal temperature was used to arrest fusion at an intermediate stage. When bundle formation was prevented by adding inhibitory peptides at this stage, membranes did not merge upon raising temperature. Inversely, when membrane merger was prevented by incorporating lysophosphatidylcholine (LPC) into cell membranes at the intermediate, the bundle did not form upon optimizing temperature. In the absence of LPC, the six-helix bundle did not form when the temperature of the intermediate was raised for times too short to promote fusion. Kinetic measures showed that after the temperature pulse, cells had not advanced further toward fusion. The latter results indicate that bundle formation is the rate-limiting step between the arrested intermediate and fusion. Electrical measures showed that the HIV Env–induced pore is initially large and grows rapidly. It is proposed that bundle formation and fusion are each contingent on the other and that movement of Env during its transition into the six-helix bundle directly induces the lipid rearrangements of membrane fusion. Because peptide inhibition showed that, at the intermediate stage, the heptad repeats of gp41 have become stably exposed, creation of the intermediate could be of importance in drug and/or vaccine development.
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spelling pubmed-21926592008-05-01 Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion Melikyan, Grigory B. Markosyan, Ruben M. Hemmati, Hila Delmedico, Mary K. Lambert, Dennis M. Cohen, Fredric S. J Cell Biol Original Article Many viral fusion proteins exhibit a six-helix bundle as a core structure. HIV Env–induced fusion was studied to resolve whether membrane merger was due to the transition into the bundle configuration or occurred after bundle formation. Suboptimal temperature was used to arrest fusion at an intermediate stage. When bundle formation was prevented by adding inhibitory peptides at this stage, membranes did not merge upon raising temperature. Inversely, when membrane merger was prevented by incorporating lysophosphatidylcholine (LPC) into cell membranes at the intermediate, the bundle did not form upon optimizing temperature. In the absence of LPC, the six-helix bundle did not form when the temperature of the intermediate was raised for times too short to promote fusion. Kinetic measures showed that after the temperature pulse, cells had not advanced further toward fusion. The latter results indicate that bundle formation is the rate-limiting step between the arrested intermediate and fusion. Electrical measures showed that the HIV Env–induced pore is initially large and grows rapidly. It is proposed that bundle formation and fusion are each contingent on the other and that movement of Env during its transition into the six-helix bundle directly induces the lipid rearrangements of membrane fusion. Because peptide inhibition showed that, at the intermediate stage, the heptad repeats of gp41 have become stably exposed, creation of the intermediate could be of importance in drug and/or vaccine development. The Rockefeller University Press 2000-10-16 /pmc/articles/PMC2192659/ /pubmed/11038187 Text en © 2000 The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Original Article
Melikyan, Grigory B.
Markosyan, Ruben M.
Hemmati, Hila
Delmedico, Mary K.
Lambert, Dennis M.
Cohen, Fredric S.
Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title_full Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title_fullStr Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title_full_unstemmed Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title_short Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
title_sort evidence that the transition of hiv-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192659/
https://www.ncbi.nlm.nih.gov/pubmed/11038187
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