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.
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.
Thompson
P D
PD
Department of Biochemistry, College of Medicine, The University of Arizona, Tucson, Arizona 85724, USA.
Jurutka
P W
PW
Haussler
C A
CA
Whitfield
G K
GK
Haussler
M R
MR
D000494:Allosteric Regulation; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D011940:Receptor Aggregation / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D007641:Keratolytic Agents; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D004247:DNA; D002117:Calcitriol