A pathogenic human Orai1 mutation unmasks STIM1-independent rapid inactivation of Orai1 channels.

ABSTRACT: Ca²⁺ release-activated Ca²⁺ (CRAC) channels are activated by direct physical interactions between Orai1, the channel protein, and STIM1, the endoplasmic reticulum Ca²⁺ sensor. A hallmark of CRAC channels is fast Ca²⁺-dependent inactivation (CDI) which provides negative feedback to limit Ca²⁺ entry through CRAC channels. Although STIM1 is thought to be essential for CDI, its molecular mechanism remains largely unknown. Here, we examined a poorly understood gain-of-function (GOF) human Orai1 disease mutation, L138F, that causes tubular aggregate myopathy. Through pairwise mutational analysis, we determine that large amino acid substitutions at either L138 or the neighboring T92 locus located on the pore helix evoke highly Ca²⁺

SUBMITTER: Yeung PS 

PROVIDER: S-EPMC9991058 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature