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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1)
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Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1)

机译：通过基质相互作用分子1（STIM1）捕获和控制Ca2 +释放激活的Ca2 +（CRAC）通道的化学计量要求

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摘要

Store-operated Ca2+ entry depends critically on physical interactions of the endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) and the Ca2+ release-activated Ca2+ (CRAC) channel protein Oraii. Recent studies support a diffusion-trap mechanism in which ER Ca2+ depletion causes STIM1 to accumulate at ER-plasma membrane (PM) junctions, where it binds to OraM, trapping and activating mobile CRAC channels in the overlying PM. To determine the stoichiometric requirements for CRAC channel trapping and activation, we expressed mCherry-STIM1 and OraM-GFP at varying ratios in HEK cells and quantified CRAC current Ocrac) activation and the STIM1:Orai1 ratio at ER-PM junctions after store depletion. By competing for a limited amount of STIM1, high levels of Oraii reduced the junctional STIM1:Orai1 ratio to a lower limit of 0.3-0.6, indicating that binding of one to two STIMIs is sufficient to immobilize the tetrameric CRAC channel at ER-PM junctions. In cells expressing a constant amount of STIM1, CRAC current was a highly nonlinear bell-shaped function of Oraii expression and the minimum stoichiometry for channel trapping failed to evoke significant activation. Peak current occurred at a ratio of ~2 STIM1:Orai1, suggesting that maximal CRAC channel activity requires binding of eight STIMIs to each channel. Further increases in Oraii caused channel activity and fast Ca2+-dependent inactivation to decline in parallel. The data are well described by a model in which STIM1 binds to OraM with negative cooperativity and channels open with positive cooperativity as a result of stabilization of the open state by STIM1.
机译：存储操作的Ca2 +进入关键取决于内质网（ER）Ca2 +传感器基质相互作用分子1（STIM1）和Ca2 +释放激活的Ca2 +（CRAC）通道蛋白Oraii的物理相互作用。最近的研究支持一种扩散捕集机制，其中ER Ca2 +耗竭导致STIM1积聚在ER-质膜（PM）交界处，在那里它与OraM结合，从而捕获并激活上覆PM中的移动CRAC通道。为了确定CRAC通道捕获和激活的化学计量要求，我们在HEK细胞中以不同的比率表达了mCherry-STIM1和OraM-GFP，并对存储耗尽后的ER-PM连接处的CRAC当前电流（Ocrac）激活和STIM1：Orai1比率进行了定量。通过竞争有限数量的STIM1，高水平的Oraii将STIM1：Orai1的连接比例降低至0.3-0.6的下限，表明一个至两个STIMI的结合足以将四聚体CRAC通道固定在ER-PM连接处。在表达恒定量的STIM1的细胞中，CRAC电流是Oraii表达的高度非线性钟形函数，用于通道捕获的最小化学计量无法引起明显的激活。峰值电流以〜2 STIM1：Orai1的比率出现，表明最大的CRAC通道活动需要八个STIMI绑定到每个通道。 Oraii的进一步增加导致通道活性和快速的Ca2 +依赖性失活平行下降。该数据很好地描述了一个模型，在该模型中，STIM1以负协作性与OraM绑定，并且由于STIM1稳定了开放状态，因此以正协作性开放了通道。

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