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A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor

Nature Structural & Molecular Biology volume 17, pages 801–807 (2010)Cite this article

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Abstract

In the absence of ligand, some nuclear receptors, including retinoic acid receptor (RAR), act as transcriptional repressors by recruiting corepressor complexes to target genes. This constitutive repression is crucial in metazoan reproduction, development and homeostasis. However, its specific molecular determinants had remained obscure. Using structural, biochemical and cell-based assays, we show that the basal repressive activity of RAR is conferred by an extended β-strand that forms an antiparallel β-sheet with specific corepressor residues. Agonist binding induces a β-strand–to–α-helix transition that allows for helix H11 formation, which in turn provokes corepressor release, repositioning of helix H12 and coactivator recruitment. Several lines of evidence suggest that this structural switch could be implicated in the intrinsic repressor function of other nuclear receptors. Finally, we report on the molecular mechanism by which inverse agonists strengthen corepressor interaction and enhance gene silencing by RAR.

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Figure 1: Structures of RAR LBD in complex with agonist, inverse agonist or neutral antagonist ligands.
Figure 2: Comparison of CoRNR1 and CoRNR2 motifs.
Figure 3: CoRNR1 β1 residues are indispensable for corepressor recruitment by RAR.
Figure 4: RAR S3 residues are indispensable for corepressor recruitment and release.
Figure 5: Structural basis of inverse agonism in RAR.
Figure 6: Proposed model for ligand-dependent and ligand-independent corepressor recruitment by NRs based on the crystal structures of RAR and progesterone receptor (PR).

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Acknowledgements

We thank G. Labesse for helpful discussions, C. Clerte for help with time-resolved fluorescence anisotropy experiments and Mitchell Lazar (Univ. of Pennsylvania) for providing us with Gal–N-CoR constructs. We acknowledge the experimental assistance from the staff of European Synchrotron Radiation Facility (ESRF) (ID14-2 beamline) during data collection. This work was supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, Université Montpellier 1 & 2, the French National Research Agency (ANR-07-PCVI-0001-01) and the Association pour la Recherche sur le Cancer (ARC 1056). C.T. and H.G. (laboratoire labélisé) are supported by the Ligue contre le cancer. Work in the laboratories of H.G. and A.R.d.L. is supported by EPITRON, an Integrated Project funded by the European Union under the 6th Framework Programme (LSHC-CT-2005-518417).

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Author notes

  1. Albane le Maire and Catherine Teyssier: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, U554, Montpellier, France

    Albane le Maire, Catherine Teyssier, Catherine A Royer, Pierre Germain & William Bourguet

  2. Centre National de la Recherche Scientifique, UMR5048, Centre de Biochimie Structurale, Universités Montpellier 1 & 2, Montpellier, France

    Albane le Maire, Catherine Teyssier, Catherine A Royer, Pierre Germain & William Bourguet

  3. Department of Cancer Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Communauté Urbaine de Strasbourg, Illkirch, France

    Cathie Erb & Hinrich Gronemeyer

  4. Institut de Recherche en Cancérologie de Montpellier, Montpellier, France

    Marina Grimaldi & Patrick Balaguer

  5. Institut National de la Santé et de la Recherche Médicale, U896, Montpellier, France

    Marina Grimaldi & Patrick Balaguer

  6. Université Montpellier 1, Montpellier, France

    Marina Grimaldi & Patrick Balaguer

  7. Centre Régional de Lutte contre le Cancer, Val d'Aurelle Paul Lamarque, Montpellier, France

    Marina Grimaldi & Patrick Balaguer

  8. Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, Vigo, Spain

    Susana Alvarez & Angel R de Lera

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Contributions

A.l.M., C.T. and W.B. purified proteins and grew crystals; A.l.M. and W.B. solved the structures; A.l.M., C.T. and C.A.R performed fluorescence anisotropy experiments; C.T., C.E., M.G., P.B. and H.G. made the DNA constructs; S.A. and A.R.d.L. synthesized BMS493; C.T. performed cell-based assays; P.G. analyzed data; W.B. planned the project, analyzed the data and wrote the manuscript; H.G. and C.A.R. edited the manuscript; all authors commented on the manuscript.

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Correspondence to William Bourguet.

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le Maire, A., Teyssier, C., Erb, C. et al. A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor. Nat Struct Mol Biol 17, 801–807 (2010). https://doi.org/10.1038/nsmb.1855

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