TY - JOUR
T1 - 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
AU - Thompson, Paul D.
AU - Jurutka, Peter W.
AU - Haussler, Carol A.
AU - Whitfield, G. Kerr
AU - Haussler, Mark R.
PY - 1998/4/3
Y1 - 1998/4/3
N2 - Gel mobility shift analysis was utilized to investigate the molecular function of 1α,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 ms 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 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 allosterie switch in VDR to a form that not only binds to the VDRE with affinity and specificity as a heterodimer with RXR, but also interacts with the RXR partner to conformationally restrict the action of its cognate ligand.
AB - Gel mobility shift analysis was utilized to investigate the molecular function of 1α,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 ms 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 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 allosterie switch in VDR to a form that not only binds to the VDRE with affinity and specificity as a heterodimer with RXR, but also interacts with the RXR partner to conformationally restrict the action of its cognate ligand.
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U2 - 10.1074/jbc.273.14.8483
DO - 10.1074/jbc.273.14.8483
M3 - Article
C2 - 9525962
AN - SCOPUS:0032478824
SN - 0021-9258
VL - 273
SP - 8483
EP - 8491
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -