Structural insights into the cooperative interaction of the intrinsically disordered co-activator TIF2 with retinoic acid receptor heterodimer (RXR/RAR)

Senicourt, L.; le Maire, A.; Allemand, F.; Carvalho, J. E.; Guee, L.; Germain, P.; Schubert, M.; Bernado, P.; Bourguet, W.; Sibille, N.

doi:10.1101/2020.10.28.359091

bioRxiv · 10.1101/2020.10.28.359091

Structural insights into the cooperative interaction of the intrinsically disordered co-activator TIF2 with retinoic acid receptor heterodimer (RXR/RAR)

Senicourt, L.·le Maire, A.·Allemand, F.·Carvalho, J. E.·Guee, L.·Germain, P.·Schubert, M.·Bernado, P.·Bourguet, W.·Sibille, N.

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Abstract

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 (TIF2NRID) containing three highly conserved -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 TIF2NRID by integrating several experimental (NMR, SAXS, 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 TIF2NRID in complex with RXR/RAR reveal a cooperative binding of the three NR-boxes as well as an active role of their flanking regions in the interaction.

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Senicourt, L., le Maire, A., Allemand, F., Carvalho, J. E., Guee, L., Germain, P., Schubert, M., Bernado, P., Bourguet, W., Sibille, N.. 2020-10-28. Structural insights into the cooperative interaction of the intrinsically disordered co-activator TIF2 with retinoic acid receptor heterodimer (RXR/RAR). https://doi.org/10.1101/2020.10.28.359091

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