title: Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering.
abstract: Whole genome duplications (WGDs) have been classically associated with the origin of evolutionary novelties and the so-called duplication-degeneration-complementation model describes the possible fates of genes after duplication. However, how sequence divergence effectively allows functional changes between gene duplicates is still unclear. In the vertebrate lineage, two rounds of WGDs took place, giving rise to paralogous gene copies observed for many gene families. For the retinoic acid receptors (RARs), for example, which are members of the nuclear hormone receptor (NR) superfamily, a unique ancestral gene has been duplicated resulting in three vertebrate paralogues: RARα, RARβ and RARγ. It has previously been shown that this single ancestral RAR was neofunctionalized to give rise to a larger substrate specificity range in the RARs of extant jawed vertebrates (also called gnathostomes). To understand RAR diversification, the members of the cyclostomes (lamprey and hagfish), jawless vertebrates representing the extant sister group of gnathostomes, provide an intermediate situation and thus allow the characterization of the evolutionary steps that shaped RAR ligand-binding properties following the WGDs. In this study, we assessed the ligand-binding specificity of cyclostome RARs and found that their ligand-binding pockets resemble those of gnathostome RARα and RARβ. In contrast, none of the cyclostome receptors studied showed any RARγ-like specificity. Together, our results suggest that cyclostome RARs cover only a portion of the specificity repertoire of the ancestral gnathostome RARs and indicate that the establishment of ligand-binding specificity was a stepwise event. This iterative process thus provides a rare example for the diversification of receptor-ligand interactions of NRs following WGDs.
authors.affiliation: Molecular Zoology Team, Institut de Génomique Fonctionnelle de Lyon , Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon , 46 Allée d'Italie, 69364 Lyon Cedex 07 , France.
authors.forename: Juliana
authors.initials: J
authors.lastname: Gutierrez-Mazariegos
authors.affiliation: Centre de Biochimie Structurale, Inserm U1054, CNRS UMR 5048 , Université de Montpellier , 29 Rue de Navacelles, 34090 Montpellier , France.
authors.forename: Eswar Kumar
authors.initials: EK
authors.lastname: Nadendla
authors.affiliation: European Molecular Biology Laboratory , European Bioinformatics Institute , (EMBL-EBI)-Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD , UK.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Studer
authors.affiliation: Departamento de Química Organica, Facultad de Química , Universidade de Vigo , 36310 Vigo , Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: Departamento de Química Organica, Facultad de Química , Universidade de Vigo , 36310 Vigo , Spain.
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
authors.affiliation: Phyloinformatics Unit , RIKEN Center for Life Science Technologies , 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 , Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Kuraku
authors.affiliation: Centre de Biochimie Structurale, Inserm U1054, CNRS UMR 5048 , Université de Montpellier , 29 Rue de Navacelles, 34090 Montpellier , France.
authors.forename: William
authors.initials: W
authors.lastname: Bourguet
authors.affiliation: Sorbonne Universités, UPMC Université Paris 06, CNRS, UMR 7009, Laboratoire de Biologie du Développement de Villefranche-sur-Mer, Observatoire Océanologique de Villefranche-sur-Mer , 181 Chemin du Lazaret, 06230 Villefranche-sur-Mer , France.
authors.forename: Michael
authors.identifier: 0000-0002-2341-712X
authors.initials: M
authors.lastname: Schubert
authors.affiliation: Molecular Zoology Team, Institut de Génomique Fonctionnelle de Lyon , Université de Lyon, Université Lyon 1, CNRS, INRA, Ecole Normale Supérieure de Lyon , 46 Allée d'Italie, 69364 Lyon Cedex 07 , France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
keywords: cyclostomes; emergence of evolutionary novelty; gene and whole genome duplication; hagfish and lamprey; nuclear hormone receptor signalling; vertebrate evolution