Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.

The HIV-1 envelope glycoprotein (Env) composed of the receptor binding domain gp120 and the fusion protein subunit gp41 catalyzes virus entry and is a major target for therapeutic intervention and for neutralizing antibodies. Env interactions with cellular receptors trigger refolding of gp41, which...

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Autores principales:	Victor Buzon, Ganesh Natrajan, David Schibli, Felix Campelo, Michael M Kozlov, Winfried Weissenhorn
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d642bbbc55a1477d878fab8a83d1108e
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spelling	oai:doaj.org-article:d642bbbc55a1477d878fab8a83d1108e2021-12-02T20:00:42ZCrystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.1553-73661553-737410.1371/journal.ppat.1000880https://doaj.org/article/d642bbbc55a1477d878fab8a83d1108e2010-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20463810/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The HIV-1 envelope glycoprotein (Env) composed of the receptor binding domain gp120 and the fusion protein subunit gp41 catalyzes virus entry and is a major target for therapeutic intervention and for neutralizing antibodies. Env interactions with cellular receptors trigger refolding of gp41, which induces close apposition of viral and cellular membranes leading to membrane fusion. The energy released during refolding is used to overcome the kinetic barrier and drives the fusion reaction. Here, we report the crystal structure at 2 A resolution of the complete extracellular domain of gp41 lacking the fusion peptide and the cystein-linked loop. Both the fusion peptide proximal region (FPPR) and the membrane proximal external region (MPER) form helical extensions from the gp41 six-helical bundle core structure. The lack of regular coiled-coil interactions within FPPR and MPER splay this end of the structure apart while positioning the fusion peptide towards the outside of the six-helical bundle and exposing conserved hydrophobic MPER residues. Unexpectedly, the section of the MPER, which is juxtaposed to the transmembrane region (TMR), bends in a 90 degrees-angle sideward positioning three aromatic side chains per monomer for membrane insertion. We calculate that this structural motif might facilitate the generation of membrane curvature on the viral membrane. The presence of FPPR and MPER increases the melting temperature of gp41 significantly in comparison to the core structure of gp41. Thus, our data indicate that the ordered assembly of FPPR and MPER beyond the core contributes energy to the membrane fusion reaction. Furthermore, we provide the first structural evidence that part of MPER will be membrane inserted within trimeric gp41. We propose that this framework has important implications for membrane bending on the viral membrane, which is required for fusion and could provide a platform for epitope and lipid bilayer recognition for broadly neutralizing gp41 antibodies.Victor BuzonGanesh NatrajanDavid SchibliFelix CampeloMichael M KozlovWinfried WeissenhornPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 6, Iss 5, p e1000880 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Victor Buzon Ganesh Natrajan David Schibli Felix Campelo Michael M Kozlov Winfried Weissenhorn Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
description	The HIV-1 envelope glycoprotein (Env) composed of the receptor binding domain gp120 and the fusion protein subunit gp41 catalyzes virus entry and is a major target for therapeutic intervention and for neutralizing antibodies. Env interactions with cellular receptors trigger refolding of gp41, which induces close apposition of viral and cellular membranes leading to membrane fusion. The energy released during refolding is used to overcome the kinetic barrier and drives the fusion reaction. Here, we report the crystal structure at 2 A resolution of the complete extracellular domain of gp41 lacking the fusion peptide and the cystein-linked loop. Both the fusion peptide proximal region (FPPR) and the membrane proximal external region (MPER) form helical extensions from the gp41 six-helical bundle core structure. The lack of regular coiled-coil interactions within FPPR and MPER splay this end of the structure apart while positioning the fusion peptide towards the outside of the six-helical bundle and exposing conserved hydrophobic MPER residues. Unexpectedly, the section of the MPER, which is juxtaposed to the transmembrane region (TMR), bends in a 90 degrees-angle sideward positioning three aromatic side chains per monomer for membrane insertion. We calculate that this structural motif might facilitate the generation of membrane curvature on the viral membrane. The presence of FPPR and MPER increases the melting temperature of gp41 significantly in comparison to the core structure of gp41. Thus, our data indicate that the ordered assembly of FPPR and MPER beyond the core contributes energy to the membrane fusion reaction. Furthermore, we provide the first structural evidence that part of MPER will be membrane inserted within trimeric gp41. We propose that this framework has important implications for membrane bending on the viral membrane, which is required for fusion and could provide a platform for epitope and lipid bilayer recognition for broadly neutralizing gp41 antibodies.
format	article
author	Victor Buzon Ganesh Natrajan David Schibli Felix Campelo Michael M Kozlov Winfried Weissenhorn
author_facet	Victor Buzon Ganesh Natrajan David Schibli Felix Campelo Michael M Kozlov Winfried Weissenhorn
author_sort	Victor Buzon
title	Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
title_short	Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
title_full	Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
title_fullStr	Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
title_full_unstemmed	Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.
title_sort	crystal structure of hiv-1 gp41 including both fusion peptide and membrane proximal external regions.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/d642bbbc55a1477d878fab8a83d1108e
work_keys_str_mv	AT victorbuzon crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions AT ganeshnatrajan crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions AT davidschibli crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions AT felixcampelo crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions AT michaelmkozlov crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions AT winfriedweissenhorn crystalstructureofhiv1gp41includingbothfusionpeptideandmembraneproximalexternalregions
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Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions.

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