The STIM-Orai coupling interface and gating of the Orai1 channel.
The STIM-Orai coupling interface and gating of the Orai1 channel.
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DOI：
10.1016/j.ceca.2017.01.001
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发表时间：
2017-05
期刊：
影响因子：
4
通讯作者：
Gill DL
中科院分区：
文献类型：
--
作者：
Zhou Y;Cai X;Nwokonko RM;Loktionova NA;Wang Y;Gill DL
在几乎所有的细胞中，钙库操纵的Ca 2+进入信号在控制一系列功能中至关重要。这些信号由ER中的STIM蛋白和PM中的奥赖通道介导，它们在离散的ER-PM连接区域内经历动态偶联过程。这种偶联是通过消耗ER储存的Ca 2+引发STIM蛋白进行复杂的激活过程而启动的。此后，STIM蛋白被捕获在ER-PM连接处，在那里它们束缚并门控PM奥赖Ca 2+通道。STIM 1以二聚体形式存在，其中单个STIM-Orai激活区（SOAR）埋藏在激活后暴露的静息蛋白中。SOAR上的暴露区域包括Phe-394残基形成了关键的Orai 1相互作用位点。使用二聚体SOAR串联体，我们揭示了Orai 1激活所需的SOAR二聚体中的两个位点中的一个。SOAR与Orai 1的这种单分子相互作用表明，STIM 1可以交联奥赖通道，对Ca 2+信号传导具有重要意义。Orai 1中靠近STIM 1结合位点的关键“连接”区域可以突变以组成性激活模拟STIM 1的门控作用的通道。这表明STIM 1通过由STIM 1仅结合至Orai 1通道的暴露C末端尾部触发的变构开关远程控制Orai 1通道门控。
In virtually all cells, store-operated Ca2+ entry signals are vital in controlling a spectrum of functions. The signals are mediated by STIM proteins in the ER and Orai channels in the PM which undergo a dynamic coupling process within discrete ER-PM junctional regions. This coupling is initiated by depletion of ER stored Ca2+ triggering STIM proteins to undergo an intricate activation process. Thereafter, STIM proteins become trapped in the ER-PM junctions where they tether and gate PM Orai Ca2+ channels. STIM1 exists as a dimer, with a single STIM-Orai activating region (SOAR) buried in the resting protein that becomes exposed upon activation. An exposed region on SOAR including the Phe-394 residue forms a critical Orai1 interacting site. Using dimeric SOAR concatemers, we reveal only one of the two sites in the SOAR dimer is needed for Orai1 activation. This unimolecular interaction of SOAR with Orai1 suggests STIM1 can cross-link Orai channels with important significance for Ca2+ signaling. A critical “nexus” region in Orai1 close to the STIM1-binding site can be mutated to constitutively activate the channel mimicking the gating action of STIM1. This indicates STIM1 remotely controls Orai1 channel gating through an allosteric switch triggered by STIM1 binding only to the exposed C-terminal tail of the Orai1 channel.