Palty Raz, Isacoff Ehud Y
From the Department of Molecular and Cell Biology and.
From the Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720 and the Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720
J Biol Chem. 2016 Jan 1;291(1):334-41. doi: 10.1074/jbc.M115.685289. Epub 2015 Nov 6.
Calcium flux through store-operated calcium entry is a central regulator of intracellular calcium signaling. The two key components of the store-operated calcium release-activated calcium channel are the Ca(2+)-sensing protein stromal interaction molecule 1 (STIM1) and the channel pore-forming protein Orai1. During store-operated calcium entry activation, calcium depletion from the endoplasmic reticulum triggers a series of conformational changes in STIM1 that unmask a minimal Orai1-activating domain (CRAC activation region (CAD)). To gate Orai1 channels, the exposed STIM1-activating domain binds to two sites in Orai1, one in the N terminus and one in the C terminus. Whether the two sites operate as distinct binding domains or cooperate in CAD binding is unknown. In this study, we show that the N and C-terminal domains of Orai1 synergistically contribute to the interaction with STIM1 and couple STIM1 binding with channel gating and modulation of ion selectivity.
通过储存性钙内流的钙通量是细胞内钙信号传导的核心调节因子。储存性钙释放激活钙通道的两个关键成分是Ca(2+) 传感蛋白基质相互作用分子1(STIM1)和通道孔形成蛋白Orai1。在储存性钙内流激活过程中,内质网钙耗竭会引发STIM1的一系列构象变化,从而暴露出一个最小的Orai1激活结构域(CRAC激活区域(CAD))。为了开启Orai1通道,暴露的STIM1激活结构域与Orai1中的两个位点结合,一个在N端,一个在C端。这两个位点是作为不同的结合结构域起作用还是在CAD结合中协同作用尚不清楚。在本研究中,我们表明Orai1的N端和C端结构域协同促进与STIM1的相互作用,并将STIM1结合与通道开启及离子选择性调节相偶联。