Structural and functional characterization of a novel type of ligand-independent RXR-USP receptor

Authors

  • Thomas Iwema,

    1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), (UMR7104 CNRS, U596 INSERM, ULP), Département de Biologie et de Génomique Structurales, Illkirch, France
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    • These authors contributed equally to this work
    • Present address: IBS (Institut de Biologie Structurale), LCCP, 41, rue Jules Horowitz, 38027 Grenoble Cedex 1, France
  • Isabelle ML Billas,

    1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), (UMR7104 CNRS, U596 INSERM, ULP), Département de Biologie et de Génomique Structurales, Illkirch, France
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    • These authors contributed equally to this work
  • Yannick Beck,

    1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), (UMR7104 CNRS, U596 INSERM, ULP), Département de Biologie et de Génomique Structurales, Illkirch, France
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  • François Bonneton,

    1. Université de Lyon, Université Lyon 1, Ecole Normale Supérieure de Lyon, IGFL, CNRS UMR5242, INRA UMR1237, IFR128, Lyon, France
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  • Hélène Nierengarten,

    1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), (UMR7104 CNRS, U596 INSERM, ULP), Département de Biologie et de Génomique Structurales, Illkirch, France
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  • Arnaud Chaumot,

    1. Université de Lyon, Université Lyon 1, Ecole Normale Supérieure de Lyon, IGFL, CNRS UMR5242, INRA UMR1237, IFR128, Lyon, France
    2. CEMAGREF, Laboratoire d'Ecotoxicologie, Lyon Cedex, France
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  • Geoff Richards,

    1. HFSP (Human Frontier Science Program), Strasbourg, France
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  • Vincent Laudet,

    Corresponding author
    1. Université de Lyon, Université Lyon 1, Ecole Normale Supérieure de Lyon, IGFL, CNRS UMR5242, INRA UMR1237, IFR128, Lyon, France
    • Corresponding authors: Laboratoire de Biologie et Génomique Structurales, IGBMC UMR7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France. Tel.: +33 388 653 220; Fax: +33 388 653 276; E-mail: moras@igbmc.u-strasbg.fr Université de Lyon, Ecole Normale Supérieure de Lyon, LBMC, CNRS UMR5161, INRA UMR1237, IFR128, 46 Allée d'Italie, Lyon Cedex 07 69364, France. Tel.: +33 472 728 190; Fax: +33 472 728 080; E-mail: vincent.laudet@ens-lyon.fr

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  • Dino Moras

    Corresponding author
    1. IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), (UMR7104 CNRS, U596 INSERM, ULP), Département de Biologie et de Génomique Structurales, Illkirch, France
    • Corresponding authors: Laboratoire de Biologie et Génomique Structurales, IGBMC UMR7104, 1 rue Laurent Fries, BP 10142, Illkirch 67404, France. Tel.: +33 388 653 220; Fax: +33 388 653 276; E-mail: moras@igbmc.u-strasbg.fr Université de Lyon, Ecole Normale Supérieure de Lyon, LBMC, CNRS UMR5161, INRA UMR1237, IFR128, 46 Allée d'Italie, Lyon Cedex 07 69364, France. Tel.: +33 472 728 190; Fax: +33 472 728 080; E-mail: vincent.laudet@ens-lyon.fr

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Abstract

Retinoid X receptor (RXR) and Ultraspiracle (USP) play a central role as ubiquitous heterodimerization partners of many nuclear receptors. While it has long been accepted that a wide range of ligands can activate vertebrate/mollusc RXRs, the existence and necessity of specific endogenous ligands activating RXR-USP in vivo is still matter of intense debate. Here we report the existence of a novel type of RXR-USP with a ligand-independent functional conformation. Our studies involved Tribolium USP (TcUSP) as representative of most arthropod RXR-USPs, with high sequence homology to vertebrate/mollusc RXRs. The crystal structure of the ligand-binding domain of TcUSP was solved in the context of the functional heterodimer with the ecdysone receptor (EcR). While EcR exhibits a canonical ligand-bound conformation, USP adopts an original apo structure. Our functional data demonstrate that TcUSP is a constitutively silent partner of EcR, and that none of the RXR ligands can bind and activate TcUSP. These findings together with a phylogenetic analysis suggest that RXR-USPs have undergone remarkable functional shifts during evolution and give insight into receptor–ligand binding evolution and dynamics.

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