title: A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.
abstract: In the absence of ligand, some nuclear receptors, including retinoic acid receptor (RAR), act as transcriptional repressors by recruiting corepressor complexes to target genes. This constitutive repression is crucial in metazoan reproduction, development and homeostasis. However, its specific molecular determinants had remained obscure. Using structural, biochemical and cell-based assays, we show that the basal repressive activity of RAR is conferred by an extended beta-strand that forms an antiparallel beta-sheet with specific corepressor residues. Agonist binding induces a beta-strand-to-alpha-helix transition that allows for helix H11 formation, which in turn provokes corepressor release, repositioning of helix H12 and coactivator recruitment. Several lines of evidence suggest that this structural switch could be implicated in the intrinsic repressor function of other nuclear receptors. Finally, we report on the molecular mechanism by which inverse agonists strengthen corepressor interaction and enhance gene silencing by RAR.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, U554, Montpellier, France.
authors.forename: Albane
authors.initials: A
authors.lastname: le Maire
authors.forename: Catherine
authors.initials: C
authors.lastname: Teyssier
authors.forename: Cathie
authors.initials: C
authors.lastname: Erb
authors.forename: Marina
authors.initials: M
authors.lastname: Grimaldi
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
authors.forename: Patrick
authors.initials: P
authors.lastname: Balaguer
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Royer
authors.forename: Pierre
authors.initials: P
authors.lastname: Germain
authors.forename: William
authors.initials: W
authors.lastname: Bourguet
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D056971:Nuclear Receptor Co-Repressor 1 / Q000737:chemistry / Q000378:metabolism; D017354:Point Mutation; D017433:Protein Structure, Secondary; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha
chemical_list: D056971:Nuclear Receptor Co-Repressor 1; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha