Nuclear hormone receptors coordinately regulate the activity of genetic networks through the recruitment of transcriptional co-regulators, including co-repressors and co-activators. Allosteric modulation of the ligand-binding domain by hormonal activators shifts the co-factor binding preference by defined structural changes in overlapping docking sites. We report here that mutations at conserved residues within the docking motif of the retinoic acid receptor α cause defects in dimerization, co-regulator association, and transcriptional regulation. Furthermore, although a minimal co-repressor receptor interaction domain is sufficient for receptor binding, flanking sequences appear to stabilize this interaction without interfering with ligand sensitivity. However, ligand sensitivity is changed by the K262A mutation, which requires much higher concentrations of all-trans-retinoic acid to promote co-repressor dissociation. Consequently, K262A functions as a dominant-negative mutant at low concentrations of all-trans-retinoic acid. As a result, transcriptional activation is mechanistically linked to co-repressor release.
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