The vitamin D hormone and its nuclear receptor: molecular actions and disease states.
The vitamin D hormone and its nuclear receptor: molecular actions and disease states.
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DOI：
10.1677/joe.0.154s057
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发表时间：
1997
期刊：
影响因子：
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通讯作者：
M. Haussler;C. Haussler;P. Jurutka;P. Thompson;J. Hsieh;L. S. Remus;S. Selznick;G. Whitfield
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文献类型：
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作者：
M. Haussler;C. Haussler;P. Jurutka;P. Thompson;J. Hsieh;L. S. Remus;S. Selznick;G. Whitfield
维生素 D 通过促进钙和磷酸盐的运输，确保这些离子的血液水平足以维持骨骼中 I 型胶原蛋白基质的正常矿化，从而在骨矿物质稳态中发挥重要作用。与典型的维生素 D 缺乏性佝偻病相反，许多维生素 D 抵抗性佝偻病综合征是由维生素代谢活化为其激素形式 1,25-二羟基维生素 D3 (1,25(OH)2D3) 或靶细胞中激素的后续功能的获得性和遗传性缺陷引起的。 1,25(OH)2D3 的作用由核维生素 D 受体 (VDR) 介导，VDR 是一种磷蛋白，以高亲和力结合激素，并通过锌指介导的 DNA 结合和蛋白质-蛋白质相互作用调节基因的表达。在遗传性低钙血症维生素 D 抵抗性佝偻病 (HVDRR) 中，人类 VDR 的自然突变使患者组织对 1,25(OH)2D3 不敏感，这对于揭示 VDR 结构功能关系特别有指导意义。这些突变分为三类：(i) DNA 结合/核定位，(ii) 激素结合和 (iii) 与类视黄醇 X 受体 (RXR) 异二聚化。所有三类 VDR 突变都会产生 HVDRR 表型，这与作为 VDR 和 RXR 的 DNA 结合、1,25(OH)2D3 配体异二聚体的活性受体的基本模型一致。维生素 D 反应元件 (VDRE) 由直接六核苷酸重复和三个核苷酸间隔区组成，已在骨中表达的正控基因（例如骨钙素、骨桥蛋白、β 3-整联蛋白和维生素 D 24-OHase）的启动子区域中被鉴定。 1,25(OH)2D3 配体促进 VDR-RXR 异二聚化和特异性、高亲和力 VDRE 结合，而 RXR 的配体 9-cis 视黄酸 (9-cis RA) 能够通过将 RXR 转移形成同二聚体来抑制 1,25(OH)2D3 刺激的转录。然而，VDR 单体的初始 1,25(OH)2D3 配体使其不仅能够将 RXR 招募到异二聚体中，而且还能在构象上沉默其 RXR 伴侣结合 9-cis RA 和解离异二聚体的能力。对蛋白质-蛋白质相互作用的进一步探测表明，VDR 还与基础转录因子 IIB (TFIIB) 结合，并且在 1,25(OH)2D3 存在的情况下，可以在溶液中产生 RXR-VDR-TFIIB 三元复合物。此外，对于 1,25(OH)2D3 的转录激活，VDR 和 RXR 都需要位于其末端 C 末端的完整短两亲性 α 螺旋（称为 AF-2）。由于 AF-2 结构域既不参与 VDR-RXR 异二聚化，也不参与 TFIIB 关联，因此推测它们以配体依赖性方式与转录共激活因子（例如类固醇受体共激活因子家族的转录共激活因子）接触，构成了 VDR 的第三种蛋白质-蛋白质相互作用。因此，在 VDR 介导的转录激活中，1,25(OH)2D3 与 VDR 的结合改变了配体结合结构域的构象，使其：(i) 与 RXR 进行强异二聚化以促进 VDRE 结合，(ii) 影响 RXR 配体结合结构域，使其抵抗 9-cis RA 的结合，但积极招募共激活剂至其 AF-2，以及 (iii) 在 VDR 中呈现 AF-2 区域对于共激活剂协会。上述事件，包括通过共激活剂与 TATA 结合蛋白和相关因子桥接，可能会定位 VDR，使其能够吸引 TFIIB 和 RNA 聚合酶 II 转录机制的平衡，最终导致含有 VDRE 的维生素 D 靶基因的重复转录起始。这样的模型可以解释 1,25(OH)2D3 通过刺激成骨细胞和破骨细胞前体基因表达来引发骨重塑的作用，同时通过诱导 24-OHase 分解代谢酶来触发其激素信号的终止。
Vitamin D plays a major role in bone mineral homeostasis by promoting the transport of calcium and phosphate to ensure that the blood levels of these ions are sufficient for the normal mineralization of type I collagen matrix in the skeleton. In contrast to classic vitamin D-deficiency rickets, a number of vitamin D-resistant rachitic syndromes are caused by acquired and hereditary defects in the metabolic activation of the vitamin to its hormonal form, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or in the subsequent functions of the hormone in target cells. The actions of 1,25(OH)2D3 are mediated by the nuclear vitamin D receptor (VDR), a phosphoprotein which binds the hormone with-high affinity and regulates the expression of genes via zinc finger-mediated DNA binding and protein-protein interactions. In hereditary hypocalcemic vitamin D-resistant rickets (HVDRR), natural mutations in human VDR that confer patients with tissue insensitivity to 1,25(OH)2D3 are particularly instructive in revealing VDR structure function relationships. These mutations fall into three categories: (i) DNA binding/nuclear localization, (ii) hormone binding and (iii) heterodimerization with retinoid X receptors (RXRs). That all three classes of VDR mutations generate the HVDRR phenotype is consistent with a basic model of the active receptor as a DNA-bound, 1,25(OH)2D3-liganded heterodimer of VDR and RXR. Vitamin D responsive elements (VDREs) consisting of direct hexanucleotide repeats with a spacer of three nucleotides have been identified in the promoter regions of positively controlled genes expressed in bone, such as osteocalcin, osteopontin, beta 3-integrin and vitamin D 24-OHase. The 1,25(OH)2D3 ligand promotes VDR-RXR heterodimerization and specific, high affinity VDRE binding, whereas the ligand for RXR, 9-cis retinoic acid (9-cis RA), is capable of suppressing 1,25(OH)2D3-stimulated transcription by diverting RXR to form homodimers. However, initial 1,25(OH)2D3 liganding of a VDR monomer renders it competent not only to recruit RXR into a heterodimer but also to conformationally silence the ability of its RXR partner to bind 9-cis RA and dissociate the heterodimer. Additional probing of protein-protein interactions has revealed that VDR also binds to basal transcription factor IIB (TFIIB) and, in the presence of 1,25(OH)2D3, an RXR-VDR-TFIIB ternary complex can be created in solution. Moreover, for transcriptional activation by 1,25(OH)2D3, both VDR and RXR require an intact short amphipathic alpha-helix, known as AF-2, positioned at their extreme C-termini. Because the AF-2 domains participate neither in VDR-RXR heterodimerization nor in TFIIB association, it is hypothesized that they contact, in a ligand-dependent fashion, transcriptional coactivators such as those of the steroid receptor coactivator family, constituting yet a third protein-protein interaction for VDR. Therefore, in VDR-mediated transcriptional activation, 1,25(OH)2D3 binding to VDR alters the conformation of the ligand binding domain such that it: (i) engages in strong heterodimerization with RXR to facilitate VDRE binding, (ii) influences the RXR ligand binding domain such that it is resistant to the binding of 9-cis RA but active in recruiting coactivator to its AF-2 and (iii) presents the AF-2 region in VDR for coactivator association. The above events, including bridging by coactivators to the TATA binding protein and associated factors, may position VDR such that it is able to attract TFIIB and the balance of the RNA polymerase II transcription machinery, culminating in repeated transcriptional initiation of VDRE-containing, vitamin D target genes. Such a model would explain the action of 1,25(OH)2D3 to elicit bone remodeling by stimulating osteoblast and osteoclast precursor gene expression, while concomitantly triggering the termination of its hormonal signal by inducing the 24-OHase catabolizing enzyme.