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

Paul D. Thompson, Peter W. Jurutka, Carol A. Haussler, G Kerr Whitfield, Mark R Haussler

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)8483-8491
Number of pages9
JournalJournal of Biological Chemistry
Volume273
Issue number14
DOIs
StatePublished - Apr 3 1998

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Vitamin D Response Element
Retinoid X Receptors
Calcitriol Receptors
Calcitriol
DNA
Ligands
Osteopontin
Osteocalcin
Retinoids
Electrophoretic Mobility Shift Assay
Ionic strength
Protein Binding
Osmolar Concentration
Rats
Gels
Switches
Association reactions
alitretinoin
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

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title = "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",
abstract = "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.",
author = "Thompson, {Paul D.} and Jurutka, {Peter W.} and Haussler, {Carol A.} and Whitfield, {G Kerr} and Haussler, {Mark R}",
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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

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AU - Jurutka, Peter W.

AU - Haussler, Carol A.

AU - Whitfield, G Kerr

AU - Haussler, Mark R

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