Abstract
Orai1, the Ca2+-selective pore in the plasma membrane, is one of the key components of the Ca2+release-activated Ca2+ (CRAC) channel complex. Activated by the Ca2+ sensor in the endoplasmic reticulum (ER) membrane, stromal interaction molecule 1 (STIM1), via direct interaction when ER luminal Ca2+ levels recede, Orai1 helps to maintain Ca2+ homeostasis within a cell. It has already been proven that the C-terminus of Orai1 is indispensable for channel activation. However, there is strong evidence that for CRAC channels to function properly and maintain all typical hallmarks, such as selectivity and reversal potential, additional parts of Orai1 are needed. In this review, we focus on these sites apart from the C-terminus; namely, the second loop and N-terminus of Orai1 and on their multifaceted role in the functioning of CRAC channels.
Highlights
Amounting approximately 1 kg of the body weight of an adult, calcium (Ca2+ ) is the most abundant mineral present within the human body, with most of it being bound within solid structures like bones and teeth
Only under conditions of low cytosolic Ca2+ levels that deprive the EF-hand domains of CRACR2A of the ion, the particular modulator was found to interact readily with stromal interaction molecule 1 (STIM1) and Orai1. This implies that the accessory protein is associated early in the activation process, while interactions with the Ca2+ release-activated Ca2+ (CRAC) channel complex disappear in further sequence when Ca2+ levels rise
STIM1 activation, involving conformational rearrangements, aggregation and translocations to prepare for direct interactions with Orai1, leading to pore opening in final consequence [11,12,13,14,15,42,170]
Summary
Amounting approximately 1 kg of the body weight of an adult, calcium (Ca2+ ) is the most abundant mineral present within the human body, with most of it being bound within solid structures like bones and teeth. The ongoing equilibration between protein-bound and free Ca2+ forces the dissociation of the ion upon store depletion [19,20,21,22,23] This serves as a trigger for a conformational opening of the N-terminal fold that is further relayed through the short transmembrane segment to the cytosolic STIM1 C-terminus which, folded towards the ER membrane upon rest, engages a more extended conformation [9,10,12,24,25,26,27]. Insights into the structure of Orai channels were highly desirable, some aspects of which will be reviewed below
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