Store-Operated Calcium Channels: From Function to Structure and Back Again
Store-Operated Calcium Channels: From Function to Structure and Back Again
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DOI：
10.1101/cshperspect.a035055
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发表时间：
2020-05-01
影响因子：
7.2
通讯作者：
Lewis, Richard S.
中科院分区：
文献类型：
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作者：
Lewis, Richard S.
钙离子内流(SOCE)是通过内质网(ER)内钙离子丢失激活的一系列离子通道发生的。其中最被理解的是钙释放激活的钙通道(CRAC)，它以其独特的激活机制、许多基本的生理功能以及由调节失调引起的各种病理而闻名。作为对内质网钙离子耗竭的响应，CRAC通道通过内质网-质膜(PM)连接处的扩散捕获机制形成，ER钙敏感基质相互作用分子(STIM)蛋白在此结合并激活Orai孔形成蛋白的六聚体以触发钙内流。细胞生物学研究正在阐明内质网-质膜连接的结构，它们在钙离子和脂质运输中的作用，以及与细胞骨架蛋白的功能相互作用。STIM和ORAI的分子结构激发了大量的诱变和电生理研究，揭示了STIM如何在非活性状态和活性状态之间切换的潜在机制，它如何结合和激活ORAI，以及STIM结合化学计量学对于开放通道和建立其标志性特征-极高的钙离子选择性和低钙电导的重要性。
Store-operated calcium (Ca2+) entry (SOCE) occurs through a widely distributed family of ion channels activated by the loss of Ca2+ from the endoplasmic reticulum (ER). The best understood of these is the Ca2+ release-activated Ca2+ (CRAC) channel, which is notable for its unique activation mechanism as well as its many essential physiological functions and the diverse pathologies that result from dysregulation. In response to ER Ca2+ depletion, CRAC channels are formed through a diffusion trap mechanism at ER-plasma membrane (PM) junctions, where the ER Ca2+-sensing stromal interaction molecule (STIM) proteins bind and activate hexamers of Orai pore-forming proteins to trigger Ca2+ entry. Cell biological studies are clarifying the architecture of ER-PM junctions, their roles in Ca2+ and lipid transport, and functional interactions with cytoskeletal proteins. Molecular structures of STIM and Orai have inspired a multitude of mutagenesis and electrophysiological studies that reveal potential mechanisms for how STIM is toggled between inactive and active states, how it binds and activates Orai, and the importance of STIM-binding stoichiometry for opening the channel and establishing its signature characteristics of extremely high Ca2+ selectivity and low Ca2+ conductance.