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| The EMBO Journal
(1997) 16, 5697–5709, doi:10.1093/emboj/16.18.5697 |
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| A mutation mimicking ligand-induced conformational change yields a constitutive RXR that senses allosteric effects in heterodimers |
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| Valerie Vivat1, Christina Zechel1, Jean-Marie Wurtz1, William Bourguet1, Hiroyuki Kagechika2, Hiroki Umemiya2, Koichi Shudo1, Dino Moras1, Hinrich Gronemeyer1 and Pierre Chambon1 |
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1 Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)/CNRS/INSERM/ULP/Collège de France, BP 163, 67404 Illkrich Cedex, CU de Strasbourg, France 2 Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan To whom correspondence should be addressed Hinrich Gronemeyer, hg@titus.u-strasbg.fr Received 2 May 1997; Revised 1 July 1997. |
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| Abstract |
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Mutations of a single residue in the retinoid X receptor  (RXR) ligand-binding pocket (LBP) generate constitutive, ligand-binding-competent mutants with structural and functional characteristics similar to those of agonist-bound wild-type RXR. Modelling of the mouse RXRF318A LBP suggests that, like agonist binding, the mutation disrupts a cluster of van der Waals interactions that maintains helix H11 in the apo-receptor location, thereby shifting the thermodynamic equilibrium to the holo form. Heterodimerization with some apo-receptors (retinoic acid, thyroid hormone and vitamin D3 receptors) results in 'silencing' of RXRF318A constitutive activity, which, on the other hand, efficiently contributes to synergistic transactivation within NGFI-B–RXR heterodimers. RAR mutants disabled for corepressor binding and/or lacking a functional AF-2 activation domain, do not relieve RXR 'silencing'. Not only RAR agonists, but also the RAR antagonist BMS614 induce conformational changes allowing RXR to exert constitutive (RXRF318A) or agonist-induced (wild-type RXR) activity in heterodimers. Interestingly, the RXRF318A constitutive activity generated within heterodimers in the presence of BMS614 requires the integrity of both RXR and RAR AF-2 domains. These observations suggest that, within RXR–RAR heterodimers, RAR can adopt a structure distinct from that of the active holo-RAR, thus allowing RXR to become transcriptionally responsive to agonists. |
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| Keywords: constitutively transcriptionally active RXR mutant, ligand-binding pocket, retinoid receptors, RXR–RAR heterodimers, RXR subordination |
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