Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced by 1,25-dihydroxyvitamin D3 and inhibited by 9-cis-retinoic acid. Evidence for allosteric receptor interactions.

Department of Biochemistry, College of Medicine, The University of Arizona, Tucson, Arizona 85724, USA.

Gel mobility shift analysis was utilized to investigate the molecular function of 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and 9-cis-retinoic acid (9-cis-RA) ligands in the binding of the vitamin D receptor (VDR) and retinoid X receptor (RXR) to mouse osteopontin and rat osteocalcin vitamin D-response elements (VDREs). At physiological ionic strength and reduced concentrations of expressed proteins, efficient binding to either VDRE occurs as a VDR. RXR heterodimer, not as a VDR homodimer. 1,25-(OH)2D3 dramatically enhances heterodimer-VDRE interaction, whereas somewhat higher concentrations of 9-cis-RA inhibit this association, perhaps related to the role of this retinoid in facilitating RXR homodimer formation. Interestingly, if VDR is occupied by 1,25-(OH)2D3 prior to complexing with RXR, the resulting heterodimer is relatively resistant to dissociation and diversion to other pathways by 9-cis-RA. Therefore, a proposed molecular action of 1,25-(OH)2D3 is to generate an allosteric switch in VDR to a form that not only binds to the VDRE with high affinity and specificity as a heterodimer with RXR, but also interacts with the RXR partner to conformationally restrict the action of its cognate ligand.

PMID: 9525962 [PubMed - indexed for MEDLINE]