Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, United States.
Elife. 2018 Aug 30;7:e36758. doi: 10.7554/eLife.36758.
The store-operated calcium (Ca) channel Orai governs Ca influx through the plasma membrane of many non-excitable cells in metazoans. The channel opens in response to the depletion of Ca stored in the endoplasmic reticulum (ER). Loss- and gain-of-function mutants of Orai cause disease. Our previous work revealed the structure of Orai with a closed pore. Here, using a gain-of-function mutation that constitutively activates the channel, we present an X-ray structure of Orai in an open conformation. Well-defined electron density maps reveal that the pore is dramatically dilated on its cytosolic side in comparison to the slender closed pore. Cations and anions bind in different regions of the open pore, informing mechanisms for ion permeation and Ca selectivity. Opening of the pore requires the release of cytosolic latches. Together with additional X-ray structures of an unlatched-but-closed conformation, we propose a sequence for store-operated activation.
钙库操纵钙通道（Orai）调控真核生物许多非兴奋性细胞的质膜钙离子内流。当内质网（ER）中储存的钙离子耗竭时，通道打开。Orai 的功能丧失和获得性突变会导致疾病。我们之前的工作揭示了具有封闭孔道的 Orai 结构。在此，我们利用一个组成性激活通道的功能获得性突变，呈现了一个处于开放构象的 Orai 的 X 射线结构。清晰的电子密度图显示，与细长的封闭孔道相比，细胞质侧的孔道明显扩张。阳离子和阴离子结合在开放孔道的不同区域，为离子渗透和 Ca 选择性提供了机制信息。孔道的打开需要释放细胞质闩锁。结合一个未闩锁但关闭构象的附加 X 射线结构，我们提出了一个钙库操纵激活的序列。
