The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

20 páginas, 7 figuras

Detalhes bibliográficos
Autores: Jiménez-Panizo, Alba, Alegre-Martí, Andrea, Tettey, Theophilus T., Fettweis, Gregory, Abella, Montserrat, Antón, Rosa, Johnson, Thomas A., Kim, Sohyoung, Schiltz, R. Louis, Núñez-Barrios, Israel, Font-Diaz, Joan, Caelles, Carme, Valledor, Annabel F., Pérez, Paloma, Rojas Mendoza, Ana M., Fernández-Recio, Juan, Presman, Diego M., Hager, Gordon L., Fuentes-Prior, Pablo, Estébanez-Perpiñá, Eva
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/286603
Acesso em linha:http://hdl.handle.net/10261/286603
Access Level:acceso abierto
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spelling The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activitiesJiménez-Panizo, AlbaAlegre-Martí, AndreaTettey, Theophilus T.Fettweis, GregoryAbella, MontserratAntón, RosaJohnson, Thomas A.Kim, SohyoungSchiltz, R. LouisNúñez-Barrios, IsraelFont-Diaz, JoanCaelles, CarmeValledor, Annabel F.Pérez, PalomaRojas Mendoza, Ana M.Fernández-Recio, JuanPresman, Diego M.Hager, Gordon L.Fuentes-Prior, PabloEstébanez-Perpiñá, Eva20 páginas, 7 figurasThe glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. We identify four distinct homodimerization interfaces on the GR-LBD surface, which can associate into 20 topologically different homodimers. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution, quantitative fluorescence microscopy in living cells, and transcriptomic analyses. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work illustrates the unique flexibility of GR's LBD and suggests different dimeric conformations within cells. In addition, we unveil pathophysiologically relevant quaternary assemblies of the receptor with important implications for glucocorticoid action and drug designE.E.-P. thanks the generosity of the Gemma E. Carretero Fund; MINECO [BFU2017-86906-R, SAF2017-71878-REDT, SAF2015-71878-REDT to E.E.-P., RTI2018-101500-B-I00 to P.F.-P., RTI2018-096735-B-100 to A.R.M., PID2019-110167RB-I00 to J.F.-R., SAF2017-89510-R to A.V.F. and C.C.]; G.L.H thanks the NIH Intramural Research Program; D.M.P was supported by CONICET. Funding for open access charge: Spanish Ministry of Science (MINECO).Peer reviewedOxford University PressMinisterio de Economía y Competitividad (España)National Institutes of Health (US)Pérez, Paloma [0000-0002-7166-2824]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/286603reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-86906-Rinfo:eu-repo/grantAgreement/MINECO//SAF2015-71878-REDTinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-101500-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110167RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89510-Rhttps://dx.doi.org/10.1093/nar/gkac1119Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2866032026-05-22T06:33:51Z
dc.title.none.fl_str_mv The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
title The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
spellingShingle The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
Jiménez-Panizo, Alba
title_short The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
title_full The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
title_fullStr The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
title_full_unstemmed The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
title_sort The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
dc.creator.none.fl_str_mv Jiménez-Panizo, Alba
Alegre-Martí, Andrea
Tettey, Theophilus T.
Fettweis, Gregory
Abella, Montserrat
Antón, Rosa
Johnson, Thomas A.
Kim, Sohyoung
Schiltz, R. Louis
Núñez-Barrios, Israel
Font-Diaz, Joan
Caelles, Carme
Valledor, Annabel F.
Pérez, Paloma
Rojas Mendoza, Ana M.
Fernández-Recio, Juan
Presman, Diego M.
Hager, Gordon L.
Fuentes-Prior, Pablo
Estébanez-Perpiñá, Eva
author Jiménez-Panizo, Alba
author_facet Jiménez-Panizo, Alba
Alegre-Martí, Andrea
Tettey, Theophilus T.
Fettweis, Gregory
Abella, Montserrat
Antón, Rosa
Johnson, Thomas A.
Kim, Sohyoung
Schiltz, R. Louis
Núñez-Barrios, Israel
Font-Diaz, Joan
Caelles, Carme
Valledor, Annabel F.
Pérez, Paloma
Rojas Mendoza, Ana M.
Fernández-Recio, Juan
Presman, Diego M.
Hager, Gordon L.
Fuentes-Prior, Pablo
Estébanez-Perpiñá, Eva
author_role author
author2 Alegre-Martí, Andrea
Tettey, Theophilus T.
Fettweis, Gregory
Abella, Montserrat
Antón, Rosa
Johnson, Thomas A.
Kim, Sohyoung
Schiltz, R. Louis
Núñez-Barrios, Israel
Font-Diaz, Joan
Caelles, Carme
Valledor, Annabel F.
Pérez, Paloma
Rojas Mendoza, Ana M.
Fernández-Recio, Juan
Presman, Diego M.
Hager, Gordon L.
Fuentes-Prior, Pablo
Estébanez-Perpiñá, Eva
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
National Institutes of Health (US)
Pérez, Paloma [0000-0002-7166-2824]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description 20 páginas, 7 figuras
publishDate 2022
dc.date.none.fl_str_mv 2022
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/286603
url http://hdl.handle.net/10261/286603
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2017-86906-R
info:eu-repo/grantAgreement/MINECO//SAF2015-71878-REDT
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-101500-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110167RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2017-89510-R
https://dx.doi.org/10.1093/nar/gkac1119
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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