Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.

RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruc...

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Detalhes bibliográficos
Autores: García-Alonso, Sara, Mesa, Pablo, Ovejero, Laura de la Puente, Aizpurua, Gonzalo, Lechuga, Carmen G, Zarzuela, Eduardo, Santiveri, Clara M, Sanclemente, Manuel, Muñoz, Javier, Musteanu, Mónica, Campos-Olivas, Ramón, Martínez-Torrecuadrada, Jorge, Barbacid, Mariano, Montoya, Guillermo
Formato: artículo
Fecha de publicación:2022
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/26791
Acesso em linha:https://hdl.handle.net/20.500.12105/26791
Access Level:acceso abierto
Palavra-chave:MAPK signaling
RAF kinases
RAF1
cancer
cryo-EM
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oai_identifier_str oai:repisalud.isciii.es:20.500.12105/26791
network_acronym_str ES
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repository_id_str
spelling Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.García-Alonso, SaraMesa, PabloOvejero, Laura de la PuenteAizpurua, GonzaloLechuga, Carmen GZarzuela, EduardoSantiveri, Clara MSanclemente, ManuelMuñoz, JavierMusteanu, MónicaCampos-Olivas, RamónMartínez-Torrecuadrada, JorgeBarbacid, MarianoMontoya, GuillermoMAPK signalingRAF kinasesRAF1cancercryo-EMRAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.Cell PressEuropean Research Council (ERC)Asociación Española contra el CáncerMinisterio de Ciencia, Innovación y Universidades (España)CRIS Cancer FoundationComunidad de Madrid (Esapña)Novo Nordisk Foundation20252025-07-0120222022-09-1520222022-09-15research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.12105/26791reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-094664-B-I00 C-RAF, UN MEDIADOR CLAVE EN TUMORES INDUCIDOS POR EL ONCOGEN K-RAS: ESTRATEGIAS TERAPEUTICASEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 RTC-2017-6576-1 NUEVOS ABORDAJES EN EL TRATAMIENTO DE CANCER DE PULMONAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-094664-B-I00 C-RAF, UN MEDIADOR CLAVE EN TUMORES INDUCIDOS POR EL ONCOGEN K-RAS: ESTRATEGIAS TERAPEUTICASopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/267912026-06-12T12:43:37Z
dc.title.none.fl_str_mv Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
title Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
spellingShingle Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
García-Alonso, Sara
MAPK signaling
RAF kinases
RAF1
cancer
cryo-EM
title_short Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
title_full Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
title_fullStr Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
title_full_unstemmed Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
title_sort Structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation.
dc.creator.none.fl_str_mv García-Alonso, Sara
Mesa, Pablo
Ovejero, Laura de la Puente
Aizpurua, Gonzalo
Lechuga, Carmen G
Zarzuela, Eduardo
Santiveri, Clara M
Sanclemente, Manuel
Muñoz, Javier
Musteanu, Mónica
Campos-Olivas, Ramón
Martínez-Torrecuadrada, Jorge
Barbacid, Mariano
Montoya, Guillermo
author García-Alonso, Sara
author_facet García-Alonso, Sara
Mesa, Pablo
Ovejero, Laura de la Puente
Aizpurua, Gonzalo
Lechuga, Carmen G
Zarzuela, Eduardo
Santiveri, Clara M
Sanclemente, Manuel
Muñoz, Javier
Musteanu, Mónica
Campos-Olivas, Ramón
Martínez-Torrecuadrada, Jorge
Barbacid, Mariano
Montoya, Guillermo
author_role author
author2 Mesa, Pablo
Ovejero, Laura de la Puente
Aizpurua, Gonzalo
Lechuga, Carmen G
Zarzuela, Eduardo
Santiveri, Clara M
Sanclemente, Manuel
Muñoz, Javier
Musteanu, Mónica
Campos-Olivas, Ramón
Martínez-Torrecuadrada, Jorge
Barbacid, Mariano
Montoya, Guillermo
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv European Research Council (ERC)
Asociación Española contra el Cáncer
Ministerio de Ciencia, Innovación y Universidades (España)
CRIS Cancer Foundation
Comunidad de Madrid (Esapña)
Novo Nordisk Foundation
dc.subject.none.fl_str_mv MAPK signaling
RAF kinases
RAF1
cancer
cryo-EM
topic MAPK signaling
RAF kinases
RAF1
cancer
cryo-EM
description RAF kinases are RAS-activated enzymes that initiate signaling through the MAPK cascade to control cellular proliferation, differentiation, and survival. Here, we describe the structure of the full-length RAF1 protein in complex with HSP90 and CDC37 obtained by cryoelectron microscopy. The reconstruction reveals a RAF1 kinase with an unfolded N-lobe separated from its C-lobe. The hydrophobic core of the N-lobe is trapped in the HSP90 dimer, while CDC37 wraps around the chaperone and interacts with the N- and C-lobes of the kinase. The structure indicates how CDC37 can discriminate between the different members of the RAF family. Our structural analysis also reveals that the folded RAF1 assembles with 14-3-3 dimers, suggesting that after folding RAF1 follows a similar activation as B-RAF. Finally, disruption of the interaction between CDC37 and the DFG segment of RAF1 unveils potential vulnerabilities in attempting the pharmacological degradation of RAF1 for therapeutic purposes.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-09-15
2022
2022-09-15
2025
2025-07-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.12105/26791
url https://hdl.handle.net/20.500.12105/26791
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-094664-B-I00 C-RAF, UN MEDIADOR CLAVE EN TUMORES INDUCIDOS POR EL ONCOGEN K-RAS: ESTRATEGIAS TERAPEUTICAS
European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 695566
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 RTC-2017-6576-1 NUEVOS ABORDAJES EN EL TRATAMIENTO DE CANCER DE PULMON
Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-094664-B-I00 C-RAF, UN MEDIADOR CLAVE EN TUMORES INDUCIDOS POR EL ONCOGEN K-RAS: ESTRATEGIAS TERAPEUTICAS
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial-NoDerivatives 4.0 International
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.812429

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