Agonist-triggered modulation of the activated and silent state of the vitamin D(3) receptor by interaction with co-repressors and co-activators.

The nuclear receptor for the hormone 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), VDR, regulates gene expression via a ternary complex with the retinoid X receptor (RXR) and a 1alpha, 25(OH)(2)D(3) response element (VDRE). This complex mediates transcriptional repression through interaction with co-repressor proteins, such as NCoR, and transactivation through agonist-triggered contacts with co-activator proteins, such as SRC-1. This study demonstrates that the interaction of the VDR with NCoR results in a preferential stabilization of the VDR in a non-agonistic conformation (silent state), whereas within a complex with SRC-1 VDR is in its agonistic conformation (activated state). Helix 12 of the ligand-binding domain of the VDR was found to be a critical sensor for the differential stabilization of the activated and silent state of the receptor. VDR agonists that showed similar sensitivity in inducing VDR-RXR-VDRE complex formation were found to mediate a different dose-dependent release of NCoR from these complexes, which correlates with their ability to stabilize the silent state of the VDR in the presence of NCoR. Interestingly, up to 50 % of all VDR-NCoR complexes were found to be stable even in the presence of saturating agonist concentrations. This was confirmed by a quenching effect of overexpressed NCoR on agonist-induced gene activity mediated by VDR-RXR heterodimers. Taken together, co-activator and co-repressor proteins antagonize each other in stabilizing the activated and silent state of the receptor and modulate in this way the sensitivity and potency of the transcriptional activation by the ligand-responsive transcription factor VDR. Copyright 2000 Academic Press.