Molecular determinants of MED1 interaction with the DNA bound VDR-RXR heterodimer.
Fiche publication
Date publication
septembre 2020
Journal
Nucleic acids research
Auteurs
Membres identifiés du Cancéropôle Est :
Dr CIANFERANI Sarah, Dr KIEFFER Bruno, Dr ROCHEL-GUIBERTEAU Natacha
Tous les auteurs :
Belorusova AY, Bourguet M, Hessmann S, Chalhoub S, Kieffer B, Cianférani S, Rochel N
Lien Pubmed
Résumé
The MED1 subunit of the Mediator complex is an essential coactivator of nuclear receptor-mediated transcriptional activation. While structural requirements for ligand-dependent binding of classical coactivator motifs of MED1 to numerous nuclear receptor ligand-binding domains have been fully elucidated, the recognition of the full-length or truncated coactivator by full nuclear receptor complexes remain unknown. Here we present structural details of the interaction between a large part of MED1 comprising its structured N-terminal and the flexible receptor-interacting domains and the mutual heterodimer of the vitamin D receptor (VDR) and the retinoid X receptor (RXR) bound to their cognate DNA response element. Using a combination of structural and biophysical methods we show that the ligand-dependent interaction between VDR and the second coactivator motif of MED1 is crucial for complex formation and we identify additional, previously unseen, interaction details. In particular, we identified RXR regions involved in the interaction with the structured N-terminal domain of MED1, as well as VDR regions outside the classical coactivator binding cleft affected by coactivator recruitment. These findings highlight important roles of each receptor within the heterodimer in selective recognition of MED1 and contribute to our understanding of the nuclear receptor-coregulator complexes.
Référence
Nucleic Acids Res.. 2020 Sep 29;: