Evidence That the Transition of HIV-1 Gp41 into a Six-Helix Bundle, Not the Bundle Configuration, Induces Membrane Fusion
By G. Melikyan, R. Markosyan, H. Hemmati, Mary K. Delmedico, D. Lambert, F. S. Cohen. Journal of Cell Biology, 2000
611 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Virology
View Paper: https://www.semanticscholar.org/paper/4c717e1532b76e2c3632b297bdf4a023981c3926
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Citations in the corpus
- HIV Enters Cells via Endocytosis and Dynamin-Dependent Fusion with Endosomes (2009, positive): “By comparison, the formation of ternary Env-CD4-CR complexes abrogated the lag before cell-cell fusion ( Melikyan et al., 2000; Mkrtchyan et al., 2005).”
- Structure of the dengue virus envelope protein after membrane fusion (2004, background): “(4) Formation of trimer contacts spreads from the fusion loops at the trimer tip to domain I at the base.”