Receptors, Glucocorticoid; Ligands; Glucocorticoids; Protein Binding; Dimerization; Receptors, Glucocorticoid/metabolism; Genetics
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Jiménez-Panizo, Alba; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain ; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain ; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Alegre-Martí, Andrea; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain ; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain
Tettey, Theophilus T; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Fettweis, Grégory ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales ; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Abella, Montserrat; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain ; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain
Antón, Rosa; Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
Johnson, Thomas A; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Kim, Sohyoung; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Schiltz, R Louis; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Núñez-Barrios, Israel; Andalusian Center for Developmental Biology (CABD-CSIC). Campus Universitario Pablo de Olavide, 41013 Sevilla, Spain
Font-Díaz, Joan; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain ; Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Caelles, Carme; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain ; Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona 08028, Spain
Valledor, Annabel F; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain ; Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
Pérez, Paloma; Instituto de Biomedicina de Valencia (IBV)-CSIC, 46010, Valencia, Spain
Rojas, Ana M ; Andalusian Center for Developmental Biology (CABD-CSIC). Campus Universitario Pablo de Olavide, 41013 Sevilla, Spain
Fernández-Recio, Juan; Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC - Universidad de La Rioja - Gobierno de La Rioja, 26007 Logroño, Spain
Presman, Diego M; IFIBYNE, UBA-CONICET, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires C1428EGA, Argentina
Hager, Gordon L ; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA
Fuentes-Prior, Pablo ; Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain
Estébanez-Perpiñá, Eva ; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona (UB), 08028 Barcelona, Spain ; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona (UB), 08028 Barcelona, Spain
MINECO - Spanish Government. Ministry of Economy, Industry and Competitiveness NIH - National Institutes of Health CONICET - Consejo Nacional de Investigaciones Científicas y Técnicas MICINN - Ministerio de Ciencia e Innovacion
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