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The TAM-associated STIM1I484R mutation increases ORAI1 channel function due to a reduced STIM1 inactivation break and an absence of microtubule trapping

Published inCell calcium, vol. 105, 102615
Publication date2022-07
First online date2022-06-23
Abstract

Tubular aggregate myopathy (TAM) is a progressive skeletal muscle disease associated with gain-of-function mutations in the ER Ca2+ sensor STIM1 that mediates store-operated Ca2+ entry (SOCE) across the Ca2+-release-activated (CRAC) Ca2+ channel ORAI1. A frameshift mutation in STIM1 inactivation domain, STIM1I484R, was identified in a TAM patient and reported to decrease SOCE. Using ion imaging and electrophysiology, we show that the STIM1I484R mutation instead renders STIM1 constitutively active. STIM1I484R was less efficient than native STIM1 when expressed alone but enhanced SOCE and increased basal Ca2+ and Mn2+ influx when expressed together with ORAI1, generating larger pre-activated CRAC currents lacking slow Ca2+-dependent inhibition (SCDI). STIM1I484R was pre-recruited in plasma membrane clusters when co-expressed with ORAI1, as were mutants truncated at the frameshift residue or lacking EB-1-binding, which recapitulated STIM1I484R gain-of-function. When expressed alone in human primary myoblasts, STIM1I484R was pre-recruited in large clusters and increased basal Ca2+ entry. These observations establish that STIM1I484R confers a gain of CRAC channel function due to the loss of critical inhibitory C-terminal domains that prevent STIM1 binding to ORAI1, enable STIM1 trapping by microtubules, and mediate SCDI, providing a mechanistic explanation for the muscular defects of TAM patients bearing this mutation.

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Citation (ISO format)
KIM, Ji-Hee et al. The TAM-associated STIM1I484R mutation increases ORAI1 channel function due to a reduced STIM1 inactivation break and an absence of microtubule trapping. In: Cell calcium, 2022, vol. 105, p. 102615. doi: 10.1016/j.ceca.2022.102615
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ISSN of the journal0143-4160
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