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Dissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion.

The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state whe... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America March 4, 2014, Vol.111(9), pp.3425-3430
Main Author: Roche, Julien
Other Authors: Louis, John M , Grishaev, Alexander , Ying, Jinfa , Bax, Adriaan
Format: Electronic Article Electronic Article
Language: English
Subjects:
Rdc
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1401397111
Link: http://search.proquest.com/docview/1504739015/?pq-origsite=primo
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title: Dissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion.
format: Article
creator:
  • Roche, Julien
  • Louis, John M
  • Grishaev, Alexander
  • Ying, Jinfa
  • Bax, Adriaan
subjects:
  • Amino Acid Sequence–Genetics
  • Chromatography, Gel–Metabolism
  • Gene Components–Chemistry
  • HIV Envelope Protein Gp41–Chemistry
  • Lipid Bilayers–Chemistry
  • Models, Biological–Chemistry
  • Molecular Sequence Data–Chemistry
  • Nuclear Magnetic Resonance, Biomolecular–Chemistry
  • Protein Conformation–Chemistry
  • Protein Multimerization–Chemistry
  • Virus Internalization–Chemistry
  • Water–Chemistry
  • HIV Envelope Protein Gp41
  • Lipid Bilayers
  • Gp41 Protein, Human Immunodeficiency Virus 1
  • Water
  • 15n Relaxation
  • HIV-1 Fusion Inhibitor
  • Rdc
  • Chemical Shift
  • Hemagglutinin
ispartof: Proceedings of the National Academy of Sciences of the United States of America, March 4, 2014, Vol.111(9), pp.3425-3430
description: The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state where the ectodomains are arranged as a trimer of helical hairpins, adopting a six-helix bundle (6HB) state. Here, we show by solution NMR spectroscopy that a water-soluble 6HB gp41 ectodomain binds to zwitterionic detergents that contain phosphocholine or phosphatidylcholine head groups and phospholipid vesicles that mimic T-cell membrane composition. Binding results in the dissociation of the 6HB and the formation of a monomeric state, where its two a-helices, N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), become embedded in the lipid-water interface of the virus and host cell. The atomic structure of the gp41 ectodomain monomer, based on NOE distance restraints and residual dipolar couplings, shows that the NHR and CHR helices remain mostly intact, but they completely lose interhelical contacts. The high affinity of the ectodomain helices for phospholipid surfaces suggests that unzippering of the prehairpin intermediate leads to a state where the NHR and CHR helices become embedded in the host cell and viral membranes, respectively, thereby providing a physical force for bringing these membranes into close juxtaposition before actual fusion. hemagglutinin | HIV-1 fusion inhibitor | RDC | [sup.15]N relaxation | chemical shift www.pnas.org/cgi/doi/10.1073/pnas.1401397111
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1401397111
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleDissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion.
creatorRoche, Julien ; Louis, John M ; Grishaev, Alexander ; Ying, Jinfa ; Bax, Adriaan
contributorRoche, Julien (correspondence author) ; Roche, Julien (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, March 4, 2014, Vol.111(9), pp.3425-3430
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1401397111
subjectAmino Acid Sequence–Genetics ; Chromatography, Gel–Metabolism ; Gene Components–Chemistry ; HIV Envelope Protein Gp41–Chemistry ; Lipid Bilayers–Chemistry ; Models, Biological–Chemistry ; Molecular Sequence Data–Chemistry ; Nuclear Magnetic Resonance, Biomolecular–Chemistry ; Protein Conformation–Chemistry ; Protein Multimerization–Chemistry ; Virus Internalization–Chemistry ; Water–Chemistry ; HIV Envelope Protein Gp41 ; Lipid Bilayers ; Gp41 Protein, Human Immunodeficiency Virus 1 ; Water ; 15n Relaxation ; HIV-1 Fusion Inhibitor ; Rdc ; Chemical Shift ; Hemagglutinin
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descriptionThe envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. The actual fusion process involves a switch from a homotrimeric prehairpin intermediate conformation, consisting of parallel coiled-coil helices, to a postfusion state where the ectodomains are arranged as a trimer of helical hairpins, adopting a six-helix bundle (6HB) state. Here, we show by solution NMR spectroscopy that a water-soluble 6HB gp41 ectodomain binds to zwitterionic detergents that contain phosphocholine or phosphatidylcholine head groups and phospholipid vesicles that mimic T-cell membrane composition. Binding results in the dissociation of the 6HB and the formation of a monomeric state, where its two a-helices, N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), become embedded in the lipid-water interface of the virus and host cell. The atomic structure of the gp41 ectodomain monomer, based on NOE distance restraints and residual dipolar couplings, shows that the NHR and CHR helices remain mostly intact, but they completely lose interhelical contacts. The high affinity of the ectodomain helices for phospholipid surfaces suggests that unzippering of the prehairpin intermediate leads to a state where the NHR and CHR helices become embedded in the host cell and viral membranes, respectively, thereby providing a physical force for bringing these membranes into close juxtaposition before actual fusion. hemagglutinin | HIV-1 fusion inhibitor | RDC | [sup.15]N relaxation | chemical shift www.pnas.org/cgi/doi/10.1073/pnas.1401397111
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titleDissociation of the trimeric gp41 ectodomain at the lipid-water interface suggests an active role in HIV-1 Env-mediated membrane fusion.
authorRoche, Julien ; Louis, John M ; Grishaev, Alexander ; Ying, Jinfa ; Bax, Adriaan
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