Quantification of the vitamin D receptor-coregulator interaction.
Quantification of the vitamin D receptor-coregulator interaction.
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维生素 D 受体-辅助调节剂相互作用的量化。
DOI：
10.1021/bi801874n
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发表时间：
2009
期刊：
影响因子：
2.9
通讯作者：
Bikle,DanielD
中科院分区：
文献类型：
--
作者：
Teichert,Arnaud;Arnold,LeggyA;Otieno,Steve;Oda,Yuko;Augustinaite,Indre;Geistlinger,TimR;Kriwacki,RichardW;Guy,RKiplin;Bikle,DanielD
维生素D受体（VDR）调节多种基因，这些基因控制包括骨矿物质稳态，免疫功能和毛囊循环在内的过程。在与其天然配体1α，25（OH）2D 3结合后，VDR经历构象变化，允许辅阻遏蛋白的释放和基因转录所必需的辅激活蛋白的结合。我们报告了在两种配体（天然配体1α，25（OH）2D 3和合成的非开环甾体激动剂LG 190178）存在下，VDR与辅调节子结合基序库相互作用的首次综合评价。我们发现VDR对SRC 1、SRC 2和SRC 3的第二和第三LxxLL基序以及DRIP 205的第二LxxLL基序具有相对高的亲和力。这种模式与其他核受体相比是不同的。研究的两种激动剂的VDR辅调节因子结合亲和力模式非常相似，表明LG 190178和1α，25（OH）2D 3的生物学功能相似。在配体存在的情况下，无毛通过LxxLL基序（Hr-1）结合VDR，在配体存在和不存在的情况下抑制转录。本研究中确定的VDR结合模式可用于预测不同组织表达不同的辅助调节因子之间的功能差异，从而促进开发组织和基因特异性维生素D反应调节剂的目标。
The vitamin D receptor (VDR) regulates a diverse set of genes that control processes including bone mineral homeostasis, immune function, and hair follicle cycling. Upon binding to its natural ligand, 1α,25(OH)2D3, the VDR undergoes a conformational change that allows the release of corepressor proteins and the binding of coactivator proteins necessary for gene transcription. We report the first comprehensive evaluation of the interaction of the VDR with a library of coregulator binding motifs in the presence of two ligands, the natural ligand 1α,25(OH)2D3and a synthetic, nonsecosteroidal agonist LG190178. We show that the VDR has relatively high affinity for the second and third LxxLL motifs of SRC1, SRC2, and SRC3 and second LxxLL motif of DRIP205. This pattern is distinct in comparison to other nuclear receptors. The pattern of VDR-coregulator binding affinities was very similar for the two agonists investigated, suggesting that the biologic functions of LG190178 and 1α,25(OH)2D3are similar. Hairless binds the VDR in the presence of ligand through a LxxLL motif (Hr-1), repressing transcription in the presence and absence of ligand. The VDR binding patterns identified in this study may be used to predict functional differences among different tissues expressing different sets of coregulators, thus facilitating the goal of developing tissue- and gene-specific vitamin D response modulators.