Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
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由 STIM1 构象转换引发的由内而外的 Ca(2 ) 信号传导。
DOI：
10.1038/ncomms8826
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发表时间：
2015-07-17
影响因子：
16.6
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Ma G;Wei M;He L;Liu C;Wu B;Zhang SL;Jing J;Liang X;Senes A;Tan P;Li S;Sun A;Bi Y;Zhong L;Si H;Shen Y;Li M;Lee MS;Zhou W;Wang J;Wang Y;Zhou Y
STIM1和ORAI1介导的钙内流是哺乳动物细胞内钙内流的主要途径之一。STIM1-ORAI1偶联的分子编排是由内质网(ER)钙库耗尽以及随后STIM1 ER-腔结构域的寡聚启动的，随后STIM1-ORAI1结构域向质膜重新分布，以门控ORAI1通道。这种由内而外的钙离子信号的机制基础在很大程度上是未知的。通过利用STIM1跨膜区(STIM1-TM)中独特的功能获得突变，我们在这里证明了局部重排，而不是STIM1-TM寡聚体状态的改变，促进了细胞质近膜卷曲区域的构象变化。重要的是，我们进一步确定了STIM1细胞质结构域(STIM1-CT)中需要自我抑制的关键残基。在这些发现的基础上，我们提出了一个模型，在该模型中，STIM1-TM重组将STIM1-CT转换为扩展构象，从而将ORAI激活结构域投射到ORAI1通道。细胞内钙的耗竭诱导内质网STIM1蛋白和质膜ORAI1通道之间的相互作用，从而促进细胞内钙的进入。在这里，Ma等人。描述了一个STIM1功能增益突变体，并提出了一个控制ORAI1门控的构象开关。
Store-operated Ca2+ entry mediated by STIM1 and ORAI1 constitutes one of the major Ca2+ entry routes in mammalian cells. The molecular choreography of STIM1–ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca2+ store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca2+ signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels. Depletion of calcium from intracellular stores induces interaction between the endoplasmic reticulum STIM1 protein and the plasma membrane ORAI1 channel that facilitates cellular calcium entry. Here Ma et al. characterize a STIM1 gain-of-function mutant and propose a conformational switch that controls ORAI1 gating.