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通过 Orai 通道对钙渗透的结构洞察。

Structural Insights into Ca Permeation through Orai Channels.

机构信息

State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin 300071, China.

出版信息

Cells. 2021 Nov 6;10(11):3062. doi: 10.3390/cells10113062.

DOI:10.3390/cells10113062
PMID:34831285
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8619096/
Abstract

Orai channels belong to the calcium release-activated calcium (CRAC) channel family. Orai channels are responsible for the influx of extracellular Ca that is triggered by Ca depletion from the endoplasmic reticulum (ER); this function is essential for many types of non-excitable cells. Extensive structural and functional studies have advanced the knowledge of the molecular mechanism by which Orai channels are activated. However, the gating mechanism that allows Ca permeation through Orai channels is less well explained. Here, we reviewed and summarized the existing structural studies of Orai channels. We detailed the structural features of Orai channels, described structural comparisons of their closed and open states, and finally proposed a "push-pull" model of Ca permeation.

摘要

Orai 通道属于钙释放激活钙 (CRAC) 通道家族。Orai 通道负责细胞外 Ca 的内流,这是由内质网 (ER) 中 Ca 耗竭触发的;该功能对于许多类型的非兴奋性细胞至关重要。广泛的结构和功能研究提高了人们对 Orai 通道激活的分子机制的认识。然而,允许 Ca 通过 Orai 通道渗透的门控机制解释得还不够充分。在这里,我们回顾和总结了现有的 Orai 通道结构研究。我们详细描述了 Orai 通道的结构特征,比较了它们的关闭和开放状态的结构,并最终提出了 Ca 渗透的“推挽”模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/2d333a6cd9f6/cells-10-03062-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/9d758dc5555f/cells-10-03062-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/b64d44fc231d/cells-10-03062-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/2351517f07ad/cells-10-03062-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/2d333a6cd9f6/cells-10-03062-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/9d758dc5555f/cells-10-03062-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/b64d44fc231d/cells-10-03062-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/2351517f07ad/cells-10-03062-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d708/8619096/2d333a6cd9f6/cells-10-03062-g004.jpg

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本文引用的文献

1
CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions.CRAC 通道的开启由跨膜区和胞质区一系列 Orai1 门控检查点决定。
J Biol Chem. 2021 Jan-Jun;296:100224. doi: 10.1074/jbc.RA120.015548. Epub 2020 Dec 29.
2
Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation.冷冻电镜结构解析钙释放激活钙通道 Orai 处于开放构象。
Elife. 2020 Nov 30;9:e62772. doi: 10.7554/eLife.62772.
3
Mechanism of STIM activation.STIM激活机制。
Curr Opin Physiol. 2020 Oct;17:74-79. doi: 10.1016/j.cophys.2020.07.006.
4
Store-Operated Ca Channels: Mechanism, Function, Pharmacology, and Therapeutic Targets.储存操纵钙通道:机制、功能、药理学和治疗靶点。
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:629-654. doi: 10.1146/annurev-pharmtox-031620-105135. Epub 2020 Sep 23.
5
The basic residues in the Orai1 channel inner pore promote opening of the outer hydrophobic gate.Orai1 通道内孔中的基本残基促进了外疏水门的开启。
J Gen Physiol. 2020 Jan 6;152(1). doi: 10.1085/jgp.201912397.
6
The Orai Ca channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis.Orai 钙通道抑制剂 CM4620 靶向实质细胞和免疫细胞,以减少实验性急性胰腺炎中的炎症。
J Physiol. 2019 Jun;597(12):3085-3105. doi: 10.1113/JP277856. Epub 2019 May 22.
7
CRAC channels and disease - From human CRAC channelopathies and animal models to novel drugs.CRAC 通道与疾病——从人类 CRAC 通道病和动物模型到新型药物。
Cell Calcium. 2019 Jun;80:112-116. doi: 10.1016/j.ceca.2019.03.004. Epub 2019 Mar 11.
8
Molecular understanding of calcium permeation through the open Orai channel.钙离子通过开放的 Orai 通道通透的分子机制。
PLoS Biol. 2019 Apr 22;17(4):e3000096. doi: 10.1371/journal.pbio.3000096. eCollection 2019 Apr.
9
Gain-of-function mutations in STIM1 and ORAI1 causing tubular aggregate myopathy and Stormorken syndrome.STIM1 和 ORAI1 功能获得性突变导致管状聚集性肌病和 Stormorken 综合征。
Cell Calcium. 2018 Dec;76:1-9. doi: 10.1016/j.ceca.2018.07.008. Epub 2018 Sep 3.
10
Structures reveal opening of the store-operated calcium channel Orai.结构揭示了钙库操纵性钙通道 Orai 的开放。
Elife. 2018 Aug 30;7:e36758. doi: 10.7554/eLife.36758.