Kahlen J P, Carlberg C
Clinique de Dermatologie, Hôpital Cantonal Universitaire, CH-1211 Genève 14, Switzerland and Institut für Physiologische Chemie I, Heinrich-Heine-Universität Düsseldorf, D-40001 Düsseldorf, Germany.
Nucleic Acids Res. 1997 Nov 1;25(21):4307-13. doi: 10.1093/nar/25.21.4307.
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.
激素1α,25 - 二羟基维生素D3（VD）的基因组作用由转录因子VDR介导，VDR是核受体超家族的成员。在大多数情况下，VDR与视黄酸X受体（RXR）形成异源二聚体复合物，作用于VD靶基因启动子中称为VD反应元件（VDREs）的特定DNA序列。本研究描述了VDR DNA结合结构域的一个突变（K45A），该突变增强了VDR - RXR异源二聚体对某些VDREs的亲和力和配体反应性。与糖皮质激素受体中的同源突变（K461A）类似，这个赖氨酸残基似乎起到变构“锁”的作用。有趣的是，发现RXR的过表达会降低野生型VDR对VD的反应性和敏感性，但会增强VDRK45A的反应。此外，VDR和RXR的反式激活结构域对于获得异源二聚体对VD和9 - 顺式视黄酸（RXR配体）的反应性至关重要。这表明在测试的VDREs上，RXR是VDR的一个活跃而非沉默的伙伴。综上所述，VDR - RXR异源二聚体的反式激活可以由蛋白质 - DNA复合物的所有组分单独触发，但似乎通过变构相互作用才能达到最大效力。
