Ion Channel Biology Laboratory, AU-KBC Research Centre, Madras Institute of Technology, Anna University, Chrompet, Chennai -600 044, India.
Curr Drug Targets. 2020;21(1):55-75. doi: 10.2174/1389450120666190926150258.
Calcium (Ca2+) ion is a major intracellular signaling messenger, controlling a diverse array of cellular functions like gene expression, secretion, cell growth, proliferation, and apoptosis. The major mechanism controlling this Ca2+ homeostasis is store-operated Ca2+ release-activated Ca2+ (CRAC) channels. CRAC channels are integral membrane protein majorly constituted via two proteins, the stromal interaction molecule (STIM) and ORAI. Following Ca2+ depletion in the Endoplasmic reticulum (ER) store, STIM1 interacts with ORAI1 and leads to the opening of the CRAC channel gate and consequently allows the influx of Ca2+ ions. A plethora of studies report that aberrant CRAC channel activity due to Loss- or gain-of-function mutations in ORAI1 and STIM1 disturbs this Ca2+ homeostasis and causes several autoimmune disorders. Hence, it clearly indicates that the therapeutic target of CRAC channels provides the space for a new approach to treat autoimmune disorders.
This review aims to provide the key structural and mechanical insights of STIM1, ORAI1 and other molecular modulators involved in CRAC channel regulation.
Understanding the structure and function of the protein is the foremost step towards improving the effective target specificity by limiting their potential side effects. Herein, the review mainly focusses on the structural underpinnings of the CRAC channel gating mechanism along with its biophysical properties that would provide the solid foundation to aid the development of novel targeted drugs for an autoimmune disorder. Finally, the immune deficiencies caused due to mutations in CRAC channel and currently used pharmacological blockers with their limitation are briefly summarized.
钙离子（Ca2+）是一种主要的细胞内信号信使，控制着基因表达、分泌、细胞生长、增殖和凋亡等多种细胞功能。控制这种钙离子稳态的主要机制是储存操作的 Ca2+释放激活的 Ca2+（CRAC）通道。CRAC 通道是由两种蛋白质，基质相互作用分子（STIM）和 ORAI 组成的完整膜蛋白。内质网（ER）储存中的 Ca2+耗尽后，STIM1 与 ORAI1 相互作用，导致 CRAC 通道门打开，从而允许 Ca2+离子流入。大量研究报告称，由于 ORAI1 和 STIM1 的失活或获得功能突变导致的异常 CRAC 通道活性破坏了这种 Ca2+稳态，并导致几种自身免疫性疾病。因此，这清楚地表明，CRAC 通道的治疗靶点为治疗自身免疫性疾病提供了新的方法。
本综述旨在提供 STIM1、ORAI1 和其他参与 CRAC 通道调节的分子调节剂的关键结构和机械见解。
了解蛋白质的结构和功能是提高有效靶向特异性的首要步骤，方法是限制其潜在的副作用。本文主要侧重于 CRAC 通道门控机制的结构基础及其生物物理特性，为开发针对自身免疫性疾病的新型靶向药物提供坚实的基础。最后，简要总结了由于 CRAC 通道突变引起的免疫缺陷和目前使用的药理学阻滞剂及其局限性。
