ALLOSTERIC INTERACTION OF THE 1-ALPHA,25-DIHYDROXYVITAMIN D-3 RECEPTOR AND THE RETINOID-X-RECEPTOR ON DNA

Genomic actions of the hormone 1 alpha,25-dihydroxy-vitamin Dg (VD) ar e mediated by the transcription factor VDR, which is a member of the n uclear receptor superfamily. VDR acts in most cases as a heterodimeric complex with the retinoid X receptor (RXR) from specific DNA sequence s in the promoter of VD target genes called VD response elements (VDRE s), This study describes a mutation (K45A) of the VDR DNA binding doma in that enhances the affinity and ligand responsiveness of VDR-RXR het erodimers on some VDREs. In analogy to a homologous mutation in the gl ucocorticoid receptor (K461A), this lysine residue appears to function as an allosteric 'lock'. Interestingly, overexpression of RXR was fou nd to reduce the responsiveness and sensitivity of wild type VDR to VD , but enhance the response of VDRK45A. Moreover, the transactivation d omains of both VDR and RXR were shown to be essential for obtaining re sponsiveness of the heterodimers to VD and 9-cis retinoic acid (the RX R ligand), This indicates that RXR is an active rather than silent par tner of the VDR on the VDREs tested. Taken together, transactivation b y VDR-RXR heterodimers can be triggered individually by all components of the protein-DNA complex, but full potency appears to be reached th rough allosteric interaction.