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Endocrinology. 2014 Nov;155(11):4275-86. doi: 10.1210/en.2014-1181. Epub 2014 Aug 13.

A mollusk retinoic acid receptor (RAR) ortholog sheds light on the evolution of ligand binding.

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Molecular Zoology Team (J.G.-M., V.L.), Institut de Génomique Fonctionnelle de Lyon, Unité Mixte de Recherche 5242, Université Lyon 1, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France; Institut National de la Santé et de la Recherche Médicale Unité 1054 (E.K.N., W.B.), Centre de Biochimie Structurale, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5048, Universités Montpellier 1 and 2, 34967 Montpellier, France; CAS in Crystallography and Biophysics (E.K.N.), University of Madras, 600-005 Chennai, India; Centre of Marine and Environmental Research/Interdisciplinary Centre of Marine and Environmental Research (D.L., M.M.S., L.F.C.C.), FCUP-Department of Biology, Faculty of Sciences, University of Porto, 4050-123 Porto, Portugal; Department of Pharmaceutical Sciences (K.P., J.W.J., M.K.), School of Pharmacy, University of Maryland, Baltimore, Maryland 21201; Laboratory of Health Sciences (J.-I.N.), School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Koshien, Nishinomiya, Hyogo 663-8179, Japan; Laboratory of Hygienic Chemistry and Molecular Toxicology (Y.H., T.N.), Gifu Pharmaceutical University, Gifu 501-1196, Japan; and Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Unité Mixte de Recherche 7009, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Centre National de la Recherche Scientifique, Observatoire Océanologique de Villefranche-sur-Mer, 06230 Villefranche-sur-Mer, France.


Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms.

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