The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities
Por:
Jimenez-Panizo, A, Alegre-Marti, A, Tettey, TT, Fettweis, G, Abella, M, Anton, R, Johnson, TA, Kim, S, Schiltz, RL, Nunez-Barrios, I, Font-Diaz, J, Caelles, C, Valledor, AF, Perez, P, Rojas, AM, Fernandez-Recio, J, Presman, DM, Hager, GL, Fuentes-Prior, P, Estebanez-Perpina, E
Publicada:
1 dic 2022
Ahead of Print:
1 dic 2022
Resumen:
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.
Filiaciones:
Jimenez-Panizo, A:
Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed Univ Barcelona IBUB, Barcelona 08028, Spain
NCI, NIH, Bethesda, MD 20892 USA
Alegre-Marti, A:
Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed Univ Barcelona IBUB, Barcelona 08028, Spain
Tettey, TT:
NCI, NIH, Bethesda, MD 20892 USA
Fettweis, G:
NCI, NIH, Bethesda, MD 20892 USA
Abella, M:
Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed Univ Barcelona IBUB, Barcelona 08028, Spain
Anton, R:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Johnson, TA:
NCI, NIH, Bethesda, MD 20892 USA
Kim, S:
NCI, NIH, Bethesda, MD 20892 USA
Schiltz, RL:
NCI, NIH, Bethesda, MD 20892 USA
Nunez-Barrios, I:
CSIC, Andalusian Ctr Dev Biol CABD, Campus Univ Pablo de Olavide, Seville 41013, Spain
Font-Diaz, J:
Univ Barcelona, Fac Biol, Dept Cell Biol Physiol & Immunol, Barcelona 08028, Spain
Caelles, C:
Univ Barcelona, Fac Pharm & Food Sci, Dept Biochem & Physiol, Barcelona 08028, Spain
Valledor, AF:
Univ Barcelona, Fac Biol, Dept Cell Biol Physiol & Immunol, Barcelona 08028, Spain
Perez, P:
CSIC, Inst Biomed Valencia IBV, Valencia 46010, Spain
Rojas, AM:
CSIC, Andalusian Ctr Dev Biol CABD, Campus Univ Pablo de Olavide, Seville 41013, Spain
Fernandez-Recio, J:
Univ La Rioja, Gobierno La Rioja, CSIC, ICVV, Logrono 26007, Spain
Presman, DM:
Univ Buenos Aires, CONICET, Fac Ciencias Exactas & Nat, IFIBYNE, C1428EGA, Buenos Aires, DF, Argentina
Hager, GL:
NCI, NIH, Bethesda, MD 20892 USA
Fuentes-Prior, P:
Biomed Res Inst St Pau IIB St Pau, Barcelona 08041, Spain
Estebanez-Perpina, E:
Univ Barcelona, Fac Biol, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Univ Barcelona, Inst Biomed Univ Barcelona IBUB, Barcelona 08028, Spain
Green Published, Green Submitted
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