State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
Proc Natl Acad Sci U S A. 2012 Apr 10;109(15):5657-62. doi: 10.1073/pnas.1118947109. Epub 2012 Mar 26.
Calcium influx through the Ca(2+) release-activated Ca(2+) (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.
钙内流通过钙释放激活钙 (CRAC) 通道是许多类型细胞的基本过程。在储存耗尽后，内质网中的钙传感器 STIM1 激活质膜中的 CRAC 通道 Orai1。我们已经确定了来自人类 (hSOAR) 的 SOAR 的结构，SOAR 是 STIM1 的一部分，能够持续激活 Orai1，以及来自秀丽隐杆线虫 (ceSTIM1-CCR) 的非活性状态的完整卷曲螺旋区。我们的研究表明，形成 SOAR 二聚体是激活 Orai1 通道所必需的。破坏 SOAR 二聚化或去除正残基簇的突变会破坏 STIM1 对 Orai1 的激活。我们在 ceSTIM1-CCR 的结构中鉴定出一个可能的抑制螺旋，它与 SOAR 紧密相互作用。功能研究表明，抑制螺旋可能使 STIM1 的 C 端保持非活性状态。我们的数据使我们能够提出 STIM1 激活的模型。
