Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc

Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is o...

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Autores: Guardado-Calvo, Pablo, Bignon, Eduardo A, Stettner, Eva, Jeffers, Scott Allen, Pérez-Vargas, Jimena, Pehau-Arnaudet, Gerard, Tortoric, M Alejandra, Jestin, Jean-Luc, Tischler-Dworschak, Nicole, Rey, Félix A
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:Chile
Idioma:inglés
OAI Identifier:oai:repositorio.anid.cl:10533/220771
Acceso en línea:https://hdl.handle.net/10533/220771
Access Level:acceso abierto
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dc.title.es_CL.fl_str_mv Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
dc.title.journal.es_CL.fl_str_mv Plos Pathogens
title Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
spellingShingle Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
Guardado-Calvo, Pablo
title_short Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
title_full Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
title_fullStr Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
title_full_unstemmed Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
title_sort Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein Gc
dc.creator.none.fl_str_mv Guardado-Calvo, Pablo
Bignon, Eduardo A
Stettner, Eva
Jeffers, Scott Allen
Pérez-Vargas, Jimena
Pehau-Arnaudet, Gerard
Tortoric, M Alejandra
Jestin, Jean-Luc
Tischler-Dworschak, Nicole
Rey, Félix A
author Guardado-Calvo, Pablo
author_facet Guardado-Calvo, Pablo
Bignon, Eduardo A
Stettner, Eva
Jeffers, Scott Allen
Pérez-Vargas, Jimena
Pehau-Arnaudet, Gerard
Tortoric, M Alejandra
Jestin, Jean-Luc
Tischler-Dworschak, Nicole
Rey, Félix A
author_role author
author2 Bignon, Eduardo A
Stettner, Eva
Jeffers, Scott Allen
Pérez-Vargas, Jimena
Pehau-Arnaudet, Gerard
Tortoric, M Alejandra
Jestin, Jean-Luc
Tischler-Dworschak, Nicole
Rey, Félix A
author2_role author
author
author
author
author
author
author
author
author
description Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic beta-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha-and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single "fusion loop". We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal "tail" that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens. Keywords, KeyWords Plus:SEMLIKI-FOREST-VIRUS; BORNE ENCEPHALITIS-VIRUS; N-LINKED GLYCOSYLATION; HUMAN DENDRITIC CELLS; VALLEY FEVER VIRUS; HANTAAN-VIRUS; HEMORRHAGIC-FEVER; CRYSTAL-STRUCTURE; ELECTRON CRYOTOMOGRAPHY; PULMONARY SYNDROME
publishDate 2016
dc.date.issued.es_CL.fl_str_mv 2016
dc.date.accessioned.none.fl_str_mv 2018-10-02T18:16:01Z
2022-07-07T15:18:44Z
dc.date.available.none.fl_str_mv 2018-10-02T18:16:01Z
2022-07-07T15:18:44Z
dc.type.none.fl_str_mv Articulo
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url https://hdl.handle.net/10533/220771
dc.language.iso.none.fl_str_mv eng
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reponame: Repositorio Digital RI2.0
dc.relation.doi.es_CL.fl_str_mv 10.1371/journal.ppat.1005813
dc.relation.projectid.es_CL.fl_str_mv info:eu-repo/grantAgreement//1140050
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dc.relation.uri.es_CL.fl_str_mv https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005813
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spelling Rey, Félix ATischler-Dworschak, NicoleJestin, Jean-LucTortoric, M AlejandraPehau-Arnaudet, GerardPérez-Vargas, JimenaJeffers, Scott AllenStettner, EvaBignon, Eduardo AGuardado-Calvo, Pablo201610.1371/journal.ppat.1005813https://hdl.handle.net/10533/220771http://purl.org/coar/access_right/c_abf2Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein GcGuardado-Calvo, PabloBignon, Eduardo AStettner, EvaJeffers, Scott AllenPérez-Vargas, JimenaPehau-Arnaudet, GerardTortoric, M AlejandraJestin, Jean-LucTischler-Dworschak, NicoleRey, Félix A2018-10-02T18:16:01Z2022-07-07T15:18:44Z2018-10-02T18:16:01Z2022-07-07T15:18:44Z2016Hantaviruses are zoonotic viruses transmitted to humans by persistently infected rodents, giving rise to serious outbreaks of hemorrhagic fever with renal syndrome (HFRS) or of hantavirus pulmonary syndrome (HPS), depending on the virus, which are associated with high case fatality rates. There is only limited knowledge about the organization of the viral particles and in particular, about the hantavirus membrane fusion glycoprotein Gc, the function of which is essential for virus entry. We describe here the X-ray structures of Gc from Hantaan virus, the type species hantavirus and responsible for HFRS, both in its neutral pH, monomeric pre-fusion conformation, and in its acidic pH, trimeric post-fusion form. The structures confirm the prediction that Gc is a class II fusion protein, containing the characteristic beta-sheet rich domains termed I, II and III as initially identified in the fusion proteins of arboviruses such as alpha-and flaviviruses. The structures also show a number of features of Gc that are distinct from arbovirus class II proteins. In particular, hantavirus Gc inserts residues from three different loops into the target membrane to drive fusion, as confirmed functionally by structure-guided mutagenesis on the HPS-inducing Andes virus, instead of having a single "fusion loop". We further show that the membrane interacting region of Gc becomes structured only at acidic pH via a set of polar and electrostatic interactions. Furthermore, the structure reveals that hantavirus Gc has an additional N-terminal "tail" that is crucial in stabilizing the post-fusion trimer, accompanying the swapping of domain III in the quaternary arrangement of the trimer as compared to the standard class II fusion proteins. The mechanistic understandings derived from these data are likely to provide a unique handle for devising treatments against these human pathogens. Keywords, KeyWords Plus:SEMLIKI-FOREST-VIRUS; BORNE ENCEPHALITIS-VIRUS; N-LINKED GLYCOSYLATION; HUMAN DENDRITIC CELLS; VALLEY FEVER VIRUS; HANTAAN-VIRUS; HEMORRHAGIC-FEVER; CRYSTAL-STRUCTURE; ELECTRON CRYOTOMOGRAPHY; PULMONARY SYNDROME11400501140050virtual::47604-1WOS:000387666900002https://hdl.handle.net/10533/220771enginstname: Conicytreponame: Repositorio Digital RI2.010.1371/journal.ppat.1005813info:eu-repo/grantAgreement//1140050info:eu-repo/semantics/dataset/hdl.handle.net/10533/93477https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005813info:eu-repo/semantics/openAccessAttribution-NonCommercial-NoDerivs 3.0 Chilehttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/Mechanistic Insight into Bunyavirus-Induced Membrane Fusion from Structure-Function Analyses of the Hantavirus Envelope Glycoprotein GcPlos PathogensArticuloinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionArticulohttps://hdl.handle.net/10533/220771http://purl.org/coar/resource_type/c_2df8fbb107d704ee-bdcb-4512-a6e6-e7812b965143virtual::47604-107d704ee-bdcb-4512-a6e6-e7812b965143virtual::47604-1CC-LICENSElicense_rdfapplication/octet-stream1232https://repositorio.anid.cl/bitstreams/297637f6-df2b-44a4-9ab0-dd6c715a4866/downloadf97bcfdf58f3e17b5cec231112dab5b1MD51LICENSElicense.txttext/plain1779https://repositorio.anid.cl/bitstreams/b0366b1e-e790-49dc-a0ed-d4ca124c7871/download593a6e7305c66c56041a9f9e15a649c1MD5210533/220771oai:repositorio.anid.cl:10533/2207712023-07-24 17:45:26.937http://creativecommons.org/licenses/by-nc-nd/3.0/cl/info:eu-repo/semantics/openAccesshttps://repositorio.anid.clRepositorio ANIDaletelier@anid.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