Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1)
Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1)
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DOI：
10.1073/pnas.1118947109
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发表时间：
2012-04-10
影响因子：
11.1
通讯作者：
Shen, Yuequan
中科院分区：
文献类型：
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作者：
Yang, Xue;Jin, Hao;Shen, Yuequan
钙内流通过Ca2+释放激活Ca2+ (CRAC)通道是许多类型细胞的重要过程。当储存耗尽时，内质网中的钙传感器STIM1激活质膜中的CRAC通道Orai1。我们已经确定了智人（Homo sapiens）的SOAR （hSOAR）的结构，它是STIM1的一部分，能够组成性地激活Orai1，以及秀丽隐杆线虫（Caenorhabditis elegans）的STIM1的整个卷曲线圈区域（ceSTIM1-CCR）处于非活性状态。我们的研究表明，SOAR二聚体的形成是激活Orai1通道所必需的。破坏SOAR二聚化或移除阳性残基簇的突变会取消STIM1对Orai1的激活。我们在ceSTIM1-CCR结构中发现了一个可能与SOAR紧密相互作用的抑制螺旋。功能研究表明，抑制螺旋可能使STIM1的c端处于失活状态。我们的数据允许我们提出STIM1激活的模型。
Calcium influx through the Ca2+ release-activated Ca2+ (CRAC) channel is an essential process in many types of cells. Upon store depletion, the calcium sensor in the endoplasmic reticulum, STIM1, activates Orai1, a CRAC channel in the plasma membrane. We have determined the structures of SOAR from Homo sapiens (hSOAR), which is part of STIM1 and is capable of constitutively activating Orai1, and the entire coiled coil region of STIM1 from Caenorhabditis elegans (ceSTIM1-CCR) in an inactive state. Our studies reveal that the formation of a SOAR dimer is necessary to activate the Orai1 channel. Mutations that disrupt SOAR dimerization or remove the cluster of positive residues abolish STIM1 activation of Orai1. We identified a possible inhibitory helix within the structure of ceSTIM1-CCR that tightly interacts with SOAR. Functional studies suggest that the inhibitory helix may keep the C-terminus of STIM1 in an inactive state. Our data allowed us to propose a model for STIM1 activation.