A unique secondary-structure switch controls constitutive gene repression by retinoic acid receptor.
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.
le Maire
Albane
A
Institut National de la Santé et de la Recherche Médicale, U554, Montpellier, France.
Teyssier
Catherine
C
Erb
Cathie
C
Grimaldi
Marina
M
Alvarez
Susana
S
de Lera
Angel R
AR
Balaguer
Patrick
P
Gronemeyer
Hinrich
H
Royer
Catherine A
CA
Germain
Pierre
P
Bourguet
William
W
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
D056971:Nuclear Receptor Co-Repressor 1; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha