Structural Insights into the Interaction of the Intrinsically Disordered Co-activator TIF2 with Retinoic Acid Receptor Heterodimer (RXR/RAR)

JOURNAL OF MOLECULAR BIOLOGY

卷:433

Article

Senicourt, Lucile¹  le Maire, Albane¹  Allemand, Frederic¹  Carvalho, JoAo E.²  Guee, Laura¹  Germain, Pierre¹  Schubert, Michael³  Bernado, Pau¹  Bourguet, William¹  Sibille, Nathalie¹ 

[1] Univ Montpellier, Ctr Biochim Struct CBS, INSERM, CNRS, Montpellier, France

[2] Univ Cote Azur, Inst Res Canc & Aging IRCAN, INSERM U1081 CNRS UMR 7284, 28 Ave Valombrose, F-06107 Nice, France

[3] Sorbonne Univ, Inst Mer Villefranche, Evolut Intercellular Signaling Dev EvoInSiDe, UMR 7009 CNRS, 181 Chemin Lazaret, F-06230 Villefranche Sur Mer, France

关键词: co-activator protein;    nuclear hormone receptors;    intrinsically disordered protein;    NMR;    X-ray crystallography;   

DOI  :  10.1016/j.jmb.2021.166899

来源: Elsevier

【 摘 要 】

Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) form heterodimers that activate target gene transcription by recruiting co-activator complexes in response to ligand binding. The nuclear receptor (NR) co-activator TIF2 mediates this recruitment by interacting with the ligand-binding domain (LBD) of NRs trough the nuclear receptor interaction domain (TIF2(NRID)) containing three highly conserved alpha-helical LxxLL motifs (NR-boxes). The precise binding mode of this domain to RXR/RAR is not clear due to the disordered nature of TIF2. Here we present the structural characterization of TIF2(NRID) by integrating several experimental (NMR, SAXS, Far-UV CD, SEC-MALS) and computational data. Collectively, the data are in agreement with a largely disordered protein with partially structured regions, including the NR-boxes and their flanking regions, which are evolutionary conserved. NMR and X-ray crystallographic data on TIF2(NRID) in complex with RXR/RAR reveal a multisite binding of the three NR-boxes as well as an active role of their flanking regions in the interaction. (C) 2021 Elsevier Ltd. All rights reserved.

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