4.7 Article

Interplay of Protein Disorder in Retinoic Acid Receptor Heterodimer and Its Corepressor Regulates Gene Expression

期刊

STRUCTURE
卷 27, 期 8, 页码 1270-+

出版社

CELL PRESS
DOI: 10.1016/j.str.2019.05.001

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资金

  1. French National Research Agency [ANR-10-INBS-04-01, ANR-10-INBS-05, ANR-17-CE11-0022, ANR-14-ACHN-0016]
  2. Grenoble Alliance for Integrated Structural Cell Biology GRAL within the Grenoble Partnership for Structural Biology (PSB) [ANR-10-LABX-49-01]
  3. TGIR-RMN-THC Fr3050 CNRS
  4. Labex EpiGenMed, an Investissements d'avenir'' program [ANR-10-LABX-12-01]
  5. CNPq Programa Ciencia Sem Fronteiras [BJT 300143/2015-0]
  6. CNPq Programa Universal [420416/2016-1]
  7. FEDER-COMPETE2020
  8. FCT [LISBOA-01-0145-FEDER-007660]
  9. Agence Nationale de la Recherche (ANR) [ANR-17-CE11-0022, ANR-14-ACHN-0016] Funding Source: Agence Nationale de la Recherche (ANR)

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In its unliganded form, the retinoic acid receptor RAR) in heterodimer with the retinoid X receptor RXR) exerts a strong repressive activity facilitated by the recruitment of transcriptional corepressors in the promoter region of target genes. By integrating complementary structural, biophysical, and computational information, we demonstrate that intrinsic disorder is a required feature for the precise regulation of RAR activity. We show that structural dynamics of RAR and RXR H12 regions is an essential mechanism for RAR regulation. Unexpectedly we found that, while mainly disordered, the corepressor N-CoR presents evolutionary conserved structured regions involved in transient intramolecular contacts. In the presence of RXR/RAR, N-CoR exploits its multivalency to form a cooperative multisite complex that displays equilibrium between different conformational states that can be tuned by cognate ligands and receptor mutations. This equilibrium is key to preserving the repressive basal state while allowing the conversion to a transcriptionally active form.

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