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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Detalles Bibliográficos
Autores: Buzón Redorta, Víctor, Natrajan, Ganesh, Schibli, David, Campelo, Fèlix, Kozlov, Michael M., Weissenhorn, Winfried
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2010
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/69426
Acceso en línea:https://hdl.handle.net/2445/69426
Access Level:acceso abierto
Palabra clave:Estructura cristal·lina (Sòlids)
Membranes cel·lulars
Fusió membranària
Layer structure (Solids)
Cell membranes
Membrane fusion
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spelling Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regionsBuzón Redorta, VíctorNatrajan, GaneshSchibli, DavidCampelo, FèlixKozlov, Michael M.Weissenhorn, WinfriedEstructura cristal·lina (Sòlids)Membranes cel·lularsFusió membranàriaLayer structure (Solids)Cell membranesMembrane fusionThe 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.Public Library of Science (PLoS)2010info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/69426Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: http://dx.doi.org/10.1371/journal.ppat.1000880PLoS Pathogens, 2010, vol. 6, num. 5, p. e1000880http://dx.doi.org/10.1371/journal.ppat.1000880cc-by (c) Buzon Redorta, Víctor et al., 2010http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/694262026-05-27T06:46:51Z
dc.title.none.fl_str_mv Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions
title Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions
spellingShingle Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions
Buzón Redorta, Víctor
Estructura cristal·lina (Sòlids)
Membranes cel·lulars
Fusió membranària
Layer structure (Solids)
Cell membranes
Membrane fusion
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
dc.creator.none.fl_str_mv Buzón Redorta, Víctor
Natrajan, Ganesh
Schibli, David
Campelo, Fèlix
Kozlov, Michael M.
Weissenhorn, Winfried
author Buzón Redorta, Víctor
author_facet Buzón Redorta, Víctor
Natrajan, Ganesh
Schibli, David
Campelo, Fèlix
Kozlov, Michael M.
Weissenhorn, Winfried
author_role author
author2 Natrajan, Ganesh
Schibli, David
Campelo, Fèlix
Kozlov, Michael M.
Weissenhorn, Winfried
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Estructura cristal·lina (Sòlids)
Membranes cel·lulars
Fusió membranària
Layer structure (Solids)
Cell membranes
Membrane fusion
topic Estructura cristal·lina (Sòlids)
Membranes cel·lulars
Fusió membranària
Layer structure (Solids)
Cell membranes
Membrane fusion
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.
publishDate 2010
dc.date.none.fl_str_mv 2010
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/69426
url https://hdl.handle.net/2445/69426
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1371/journal.ppat.1000880
PLoS Pathogens, 2010, vol. 6, num. 5, p. e1000880
http://dx.doi.org/10.1371/journal.ppat.1000880
dc.rights.none.fl_str_mv cc-by (c) Buzon Redorta, Víctor et al., 2010
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Buzon Redorta, Víctor et al., 2010
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLoS)
publisher.none.fl_str_mv Public Library of Science (PLoS)
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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