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Co-regulator recruitment and the mechanism of retinoic acid receptor synergy

Nature volume 415, pages 187–192 (2002)Cite this article

Abstract

Crystal structure and co-regulator interaction studies have led to a general mechanistic view of the initial steps of nuclear receptor (NR) action. Agonist-induced transconformation of the ligand-binding domain (holo-LBD) leads to the formation of co-activator complexes, and destabilizes the co-repressor complexes bound to the ligand-free (apo) LBD1,2,3. However, the molecular basis of retinoid-X receptor (RXR) ‘subordination’ in heterodimers, an essential mechanism to avoid signalling pathway promiscuity, has remained elusive. RXR, in contrast to its heterodimer partner, cannot autonomously induce transcription on binding of cognate agonists4,5,6,7. Here we show that RXR can bind ligand and recruit co-activators as a heterodimer with apo-retinoic-acid receptor (apo-RAR). However, in the usual cellular environment co-repressors do not dissociate and they prohibit co-activator access because co-regulator binding is mutually exclusive. Accordingly, RXR subordination can be overcome in heterodimers that bind co-repressor weakly or in cells with a high co-activator content. We identify two types of RAR antagonists that differentially modulate co-regulator interaction, and we demonstrate that synergy between RAR ligands and RXR agonists6,8 results from increased interaction efficiency of a single p160 with the heterodimer, requiring two intact receptor-binding surfaces on the co-activator.

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Figure 1: Both subunits of the RAR–RXR heterodimer can interact autonomously with a single TIF2 molecule.
Figure 2: Cooperative recruitment of a single TIF2 molecule to RAR–RXR requires at least two intact NR boxes.
Figure 3: RAR–RXR heterodimer can interact with TIF2 or SMRT in the presence of the rexinoid agonists, whereas the RAR antagonists impair TIF2 interaction and can destabilize (BMS614) or stabilize (BMS493) the SMRT–heterodimer interaction.
Figure 4: Proposed model for RAR–RXR heterodimer (HD) function in the presence of agonists and two different types of antagonist.

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Acknowledgements

We thank W. Raffelsberger for providing the PCR protocols for RARβ2 promoter amplification, and N. Potier and A. van Dorsselaer for the ESI-MS analysis. We are grateful to C. Peluso-Iltis and V. Chavant for help in protein purification, C. Erb for expression vectors and A. Pornon for technical assistance. We thank W. Bourguet for critically reading this manuscript and Y. Lutz and C. Egly for antibodies. BMS-labelled retinoids/rexinoids were provided by C. Zusi, and CD3254 and AGN192870 by U. Reichert and S. Michel. This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Centre National de La Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the European Community and Bristol-Myers Squibb.

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  1. Jaya Iyer

    Present address: Monsanto Enterprises Limited, INBRI, 277 Chowdaiah Road, 18th cross Malleshwaram, Bangalore, 560003, India

  2. Christina Zechel

    Present address: Laboratory of Molecular Neurobiology, Institute of Biochemistry and Pathobiochemistry, Johannes Gutenberg University Medical School, 55099, Mainz, Germany

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, BP 163, Illkirch Cedex, C. U. de Strasbourg, F-67404, France

    Pierre Germain, Jaya Iyer, Christina Zechel & Hinrich Gronemeyer

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Correspondence to Hinrich Gronemeyer.

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Germain, P., Iyer, J., Zechel, C. et al. Co-regulator recruitment and the mechanism of retinoic acid receptor synergy. Nature 415, 187–192 (2002). https://doi.org/10.1038/415187a

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