The role of receptor topology in the vitamin D3 uptake and Ca(2+) response systems.
The role of receptor topology in the vitamin D3 uptake and Ca(2+) response systems.
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受体拓扑在维生素 D3 摄取和 Ca(2 ) 反应系统中的作用。
DOI：
10.1016/j.bbrc.2016.06.143
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发表时间：
2016
影响因子：
3.1
通讯作者：
Gupta,RajK
中科院分区：
文献类型：
--
作者：
Morrill,GeneA;Kostellow,AdeleB;Gupta,RajK
类固醇激素维生素 D3 通过至少两个受体调节基因转录，并在质膜上启动假定的快速反应系统。维生素 D 受体 (VDR) 与维生素 D3 结合，第二个受体 importin-4 通过核孔将 VDR-维生素 D3 复合物导入细胞核。在这里，我们提供的证据表明智人VDR同型二聚体包含两个跨膜（TM）螺旋（327E - D342）、两个TM“半螺旋”（264K单键N276）、一个或多个大通道以及16个胆固醇结合（CRAC/CARC）结构域。 importin-4 单体具有 3 个孔衬区域（226E – L251；768V – G783；876S – A891）和 16 个 CRAC/CARC 结构域。 MEMSAT算法表明VDR和importin-4可能不限于细胞质和细胞核。 VDR 同二聚体 TM 螺旋拓扑预测插入质膜，两个 84 残基 C 端区域位于细胞外。同样，MEMSAT 预测 importin-4 会插入质膜，具有 226 个残基细胞外 N 端区域和 96 个残基 C 端细胞外环；孔衬区域贡献门控 Ca2+ 通道。 PoreWalker算法表明，每个VDR单体的427个残基中，有91个位于最大通道，包括两个维生素D3结合位点以及来自TM螺旋和“半螺旋”的残基。胆固醇结合域也延伸到配体结合区域内的通道中。结合胆固醇的程序性变化可以调节膜Ca2+反应系统和维生素D3摄取以及内膜系统的受体内化，最终将维生素D3-VDR-importin-4复合物摄取到细胞核中。
The steroid hormone, vitamin D3, regulates gene transcription via at least two receptors and initiates putative rapid response systems at the plasma membrane. The vitamin D receptor (VDR) binds vitamin D3and a second receptor, importin-4, imports the VDR-vitamin D3complex into the nucleus via nuclear pores. Here we present evidence that theHomo sapiensVDR homodimer contains two transmembrane (TM) helices (327E – D342), two TM “half-helix” (264K single bond N276), one or more large channels, and 16 cholesterol binding (CRAC/CARC) domains. The importin-4 monomer exhibits 3 pore-lining regions (226E – L251;768V – G783;876S – A891) and 16 CRAC/CARC domains. The MEMSAT algorithm indicates that VDR and importin-4 may not be restricted to cytoplasm and nucleus. VDR homodimer TM helix-topology predicts insertion into the plasma membrane, with two 84 residue C-terminal regions being extracellular. Similarly, MEMSAT predicts importin-4 insertion into the plasma membrane with 226 residue extracellular N-terminal regions and 96 residue C-terminal extracellular loops; with the pore-lining regions contributing gated Ca2+channels. The PoreWalker algorithm indicates that, of the 427 residues in each VDR monomer, 91 line the largest channel, including two vitamin D3binding sites and residues from both the TM helix and “half-helix”. Cholesterol-binding domains also extend into the channel within the ligand binding region. Programmed changes in bound cholesterol may regulate both membraneCa2+response systems and vitamin D3uptake as well as receptor internalization by the endomembrane system culminating in uptake of the vitamin D3-VDR-importin-4 complex into the nucleus.