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

The 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...

Descripción completa

Detalles 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 Díaz, Joan, Caelles Franch, Carme, Valledor Fernández, Annabel, Pérez, Paloma, Rojas Mendoza, Ana Maria, Fernández-Recio, Juan, Presman, Diego M., Hager, Gordon L., Fuentes-Prior, Pablo, Estébanez Perpiñá, Eva
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/193850
Acceso en línea:https://hdl.handle.net/2445/193850
Access Level:acceso abierto
Palabra clave:Glucocorticoides
Metabolisme
Glucocorticoids
Metabolism
id ES_c6db2d30109aeec9472b87f4b2a625e6
oai_identifier_str oai:diposit.ub.edu:2445/193850
network_acronym_str ES
network_name_str España
repository_id_str
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 Díaz, JoanCaelles Franch, CarmeValledor Fernández, AnnabelPérez, PalomaRojas Mendoza, Ana MariaFernández-Recio, JuanPresman, Diego M.Hager, Gordon L.Fuentes-Prior, PabloEstébanez Perpiñá, EvaGlucocorticoidesMetabolismeGlucocorticoidsMetabolismThe 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 design.Oxford University Press2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/193850Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1093/nar/gkac1119Nucleic Acids Research, 2022, vol. 30, num. 22, p. 13063-13082https://doi.org/10.1093/nar/gkac1119cc-by-nc (c) Jiménez Panizo, Alba et al., 2022https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1938502026-05-27T06:46:51Z
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
Glucocorticoides
Metabolisme
Glucocorticoids
Metabolism
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 Díaz, Joan
Caelles Franch, Carme
Valledor Fernández, Annabel
Pérez, Paloma
Rojas Mendoza, Ana Maria
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 Díaz, Joan
Caelles Franch, Carme
Valledor Fernández, Annabel
Pérez, Paloma
Rojas Mendoza, Ana Maria
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 Díaz, Joan
Caelles Franch, Carme
Valledor Fernández, Annabel
Pérez, Paloma
Rojas Mendoza, Ana Maria
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.subject.none.fl_str_mv Glucocorticoides
Metabolisme
Glucocorticoids
Metabolism
topic Glucocorticoides
Metabolisme
Glucocorticoids
Metabolism
description The 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 design.
publishDate 2022
dc.date.none.fl_str_mv 2022
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/2445/193850
url https://hdl.handle.net/2445/193850
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1093/nar/gkac1119
Nucleic Acids Research, 2022, vol. 30, num. 22, p. 13063-13082
https://doi.org/10.1093/nar/gkac1119
dc.rights.none.fl_str_mv cc-by-nc (c) Jiménez Panizo, Alba et al., 2022
https://creativecommons.org/licenses/by-nc/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc (c) Jiménez Panizo, Alba et al., 2022
https://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
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
_version_ 1869419108154474496
score 15,300719

Similares en LA Referencia