Cited by 84Estrogen and related hormone effectsNuclear Receptors and SignalingProtein Structure and Dynamics

Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors

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Osz, Judit, Brélivet, Yann, Peluso-Iltis, Carole, Cura, Vincent, Eiler, Sylvia, Ruff, Marc, Bourguet, William, Rochel, Natacha +1 more·2012·Proceedings of the National Academy of Sciences

Abstract

Transcription regulation by steroid hormones, vitamin derivatives, and metabolites is mediated by nuclear receptors (NRs), which play an important role in ligand-dependent gene expression and human health. NRs function as homodimers or heterodimers and are involved in a combinatorial, coordinated and sequentially orchestrated exchange between coregulators (corepressors, coactivators). The architecture of DNA-bound functional dimers positions the coregulators proteins. We previously demonstrated that retinoic acid (RAR-RXR) and vitamin D3 receptors (VDR-RXR) heterodimers recruit only one coactivator molecule asymmetrically without steric hindrance for the binding of a second cofactor. We now address the problem of homodimers for which the presence of two identical targets enhances the functional importance of the mode of binding. Using structural and biophysical methods and RAR as a model, we could dissect the molecular mechanism of coactivator recruitment to homodimers. Our study reveals an allosteric mechanism whereby binding of a coactivator promotes formation of nonsymmetrical RAR homodimers with a 2∶1 stoichiometry. Ligand conformation and the cofactor binding site of the unbound receptor are affected through the dimer interface. A similar control mechanism is observed with estrogen receptor (ER) thus validating the negative cooperativity model for an established functional homodimer. Correlation with published data on other NRs confirms the general character of this regulatory pathway.

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Crossref · 10.1073/pnas.1118192109

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  • Upon ligand binding, RARα undergoes conformational changes that provoke corepressor release and coactivator binding.

    “Nevertheless, upon ligand binding, RAR ␣ undergoes conformational changes that provoke corepressor release and coactivator binding ( Fig. 3B ).”
  • Only one coactivator molecule is recruited by the heterodimer through the RAR partner, and the architecture of the DNA-bound receptor complexes orients the coactivator on one side of the DNA opposite to the RXR LBD and DBD so that it can reach its targets, the histone tails.

    “According to recent studies ( 87,97 ), only one coactivator molecule is recruited by the heterodimer through the RAR partner, and the architecture of the DNA-bound receptor complexes orients the coactivator on one side of the DNA opposite to the RXR LBD and DBD so that it can reach its targets, the histone tails.”

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Authors
Osz, J., Brélivet, Y., Peluso-Iltis, C., Cura, V., Eiler, S., Ruff, M., Bourguet, W., Rochel, N., & Moras, D.
Affiliations
  • Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut National de Santé et de Recherche Médicale U964/Centre National de Recherche Scientifique, Unité Mixte de Recherche 7104/Université de Strasbourg, 67404 Illkirch, France; and
  • Centre National de la Recherche Scientifique (FR)
Venue
Proceedings of the National Academy of Sciences
Published
2012-02-21
Volume
109
Issue
10
Pages
E588-94
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2003359771
Cited by
84
References
41
Citations by year
2026: 4 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 8 · 2016: 2 · 2015: 15 · 2014: 9 · 2013: 7 · 2012: 6
FWCI
7.13
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
Funders
  • European Molecular Biology Laboratory
  • Agence Nationale de la Recherche (ANR-09-BLAN-0282)
  • European Synchrotron Radiation Facility
  • Université de Strasbourg
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
nuclear receptors, allosteric regulation, coactivator recruitment, receptor homodimers, retinoic acid receptor, vitamin D receptor, estrogen receptor, cofactor binding, negative cooperativity, dimer interface, corepressors
MeSH terms
Allosteric Site, Biophysics, Cell Nucleus, Humans, Kinetics, Ligands, Models, Biological, Models, Molecular, Molecular Conformation, Peptides, Protein Binding, Receptors, Calcitriol, Receptors, Retinoic Acid, Crystallography, X-Ray, Dimerization, Nuclear Receptor Coactivator 1

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