title: Viral envelope protein folding and membrane hemifusion are enhanced by the conserved loop region of HIV-1 gp41.
abstract: Fusion of human immunodeficiency virus (HIV-1) with target cells is mediated by the gp41 transmembrane envelope protein. The loop region within gp41 contains 2 crucial cysteines that play an unknown role in HIV-cell fusion. On the basis of cell-cell fusion assay, using human T-cell lines [Jurkat E6-1 and Jurkat HXBc2(4)], and virus-cell fusion assay, using fully infectious HIV-1 HXBc2 virus and TZM-bl human cell line, we provide evidence that the oxidation state of the disulfide bond within a loop domain peptide determines its activity. The oxidized (closed) form inhibits fusion, while the reduced (opened) form enhances hemifusion. These opposite activities reach 60% difference in viral fusion. Both forms of the loop domain interact with gp41: the opened form enhances gp41 folding into a bundle, whereas the closed form inhibits this folding. Therefore, the transformation of the cysteines from a reduced to an oxidized state enables the loop to convert from opened to closed conformations, which assists gp41 to fold and induces hemifusion. The significant conservation of the loop region within many envelope proteins suggests a general mechanism, which is exploited by viruses to enhance entry into their host cells.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100 Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Ashkenazi
authors.forename: Mathias
authors.initials: M
authors.lastname: Viard
authors.forename: Yael
authors.initials: Y
authors.lastname: Wexler-Cohen
authors.forename: Robert
authors.initials: R
authors.lastname: Blumenthal
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002459:Cell Fusion; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D019169:Jurkat Cells; D007700:Kinetics; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology*; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D017510:Protein Folding; D013997:Time Factors
chemical_list: D004220:Disulfides; D015700:HIV Envelope Protein gp41; D010455:Peptides; D003545:Cysteine; D000409:Alanine