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Nucleic Acids Research, Vol 25, Issue 21 4307-4313, Copyright © 1997 by Oxford University Press

ARTICLES

Allosteric interaction of the 1alpha,25-dihydroxyvitamin D3 receptor and the retinoid X receptor on DNA

JP Kahlen and C Carlberg
Clinique de Dermatologie, Hopital Cantonal Universitaire, CH-1211 Geneve 14, Switzerland and Institut fur Physiologische Chemie I, Heinrich-Heine-Universitat Dusseldorf, D-40001 Dusseldorf, Germany.

Genomic actions of the hormone 1alpha,25-dihydroxy-vitamin D3(VD) are mediated by the transcription factor VDR, which is a member of the nuclear receptor superfamily. VDR acts in most cases as a heterodimeric complex with the retinoid X receptor (RXR) from specific DNA sequences in the promoter of VD target genes called VD response elements (VDREs). This study describes a mutation (K45A) of the VDR DNA binding domain that enhances the affinity and ligand responsiveness of VDR-RXR heterodimers on some VDREs. In analogy to a homologous mutation in the glucocorticoid receptor (K461A), this lysine residue appears to function as an allosteric 'lock'. Interestingly, overexpression of RXR was found to reduce the responsiveness and sensitivity of wild type VDR to VD, but enhance the response of VDRK45A. Moreover, the transactivation domains of both VDR and RXR were shown to be essential for obtaining responsiveness of the heterodimers to VD and 9- cis retinoic acid (the RXR ligand). This indicates that RXR is an active rather than silent partner of the VDR on the VDREs tested. Taken together, transactivation by VDR-RXR heterodimers can be triggered individually by all components of the protein-DNA complex, but full potency appears to be reached through allosteric interaction.
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