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Orai通道C末端肽是STIM-Orai偶联和钙信号产生的关键调节因子。

Orai channel C-terminal peptides are key modulators of STIM-Orai coupling and calcium signal generation.

作者信息

Baraniak James H, Zhou Yandong, Nwokonko Robert M, Jennette Michelle R, Kazzaz Sarah A, Stenson Jazmin M, Whitsell Abigale L, Wang Youjun, Trebak Mohamed, Gill Donald L

机构信息

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.

出版信息

Cell Rep. 2021 Jun 29;35(13):109322. doi: 10.1016/j.celrep.2021.109322.

DOI:10.1016/j.celrep.2021.109322
PMID:34192542
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8462482/
Abstract

Junctional coupling between endoplasmic reticulum (ER) Ca-sensor STIM proteins and plasma membrane (PM) Orai channels mediates Ca signals in most cells. We reveal that PM-tethered, fluorescently tagged C-terminal M4x (fourth transmembrane helix contains a cytoplasmic C-terminal extension) peptides from Orai channels undergo a Leu-specific signature of direct interaction with the STIM1 Orai-activating region (SOAR), exactly mimicking STIM1 binding to gate Orai channels. The 20-amino-acid Orai3-M4x peptide associates avidly with STIM1 within ER-PM junctions, functions to competitively block native Ca signals, and mediates a key modification of STIM-Orai coupling induced by 2-aminoethoxydiphenyl borate. By blocking STIM-Orai coupling, the Orai3-M4x peptide reveals the critical role of Orai channels in driving Ca oscillatory signals and transcriptional control through NFAT. The M4x peptides interact independently with SOAR dimers consistent with unimolecular coupling between Orai subunits and STIM1 dimers. We reveal the critical role of M4x helices in defining the coupling interface between STIM and Orai proteins to mediate store-operated Ca signals.

摘要

内质网（ER）钙传感器STIM蛋白与质膜（PM）Orai通道之间的连接偶联介导了大多数细胞中的钙信号。我们发现，来自Orai通道的质膜锚定、荧光标记的C末端M4x（第四个跨膜螺旋包含一个细胞质C末端延伸）肽与STIM1 Orai激活区域（SOAR）发生亮氨酸特异性直接相互作用，精确模拟了STIM1与Orai通道门控的结合。20个氨基酸的Orai3-M4x肽在内质网-质膜连接处与STIM1紧密结合，起到竞争性阻断天然钙信号的作用，并介导由2-氨基乙氧基二苯硼酸盐诱导的STIM-Orai偶联的关键修饰。通过阻断STIM-Orai偶联，Orai3-M4x肽揭示了Orai通道在驱动钙振荡信号和通过NFAT进行转录控制中的关键作用。M4x肽与SOAR二聚体独立相互作用，这与Orai亚基和STIM1二聚体之间的单分子偶联一致。我们揭示了M4x螺旋在定义STIM和Orai蛋白之间的偶联界面以介导储存式钙信号中的关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cae/8462482/cf83d2afc976/nihms-1720097-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cae/8462482/3be1c887bea1/nihms-1720097-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cae/8462482/093d4a2e45e3/nihms-1720097-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cae/8462482/cf83d2afc976/nihms-1720097-f0007.jpg

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