The Intramolecular Interaction Of IDstim Within STIM1 Prevents A Spontaneous Ca2+ Entry

Abstract

SOCE (store-operated calcium entry) is a major calcium ion influx pathway and abnormal SOCE activation causes severe diseases such as Stormorken syndrome, York platelet syndrome, and tubular aggregate myopathy. To control SOCE, STIM1 undergoes a conformational change in its cytosolic domains. STIM1 was known to maintain an inactive state through hydrophobic interaction between CC1 (coiled-coil domain 1) and CAD (CRAC activating domain). However, the CC1-CAD fragment showed constitutive activation despite maintaining the hydrophobic interaction. This conflicting observation implies that an additional mechanism is required to maintain the inactive state of STIM1. Here, we show that IDstim (inactivation domain of STIM1) binds to and inhibits CC1-CAD and this inhibitory effect of IDstim is abolished by either CC1α1 deletion or leucine substitution. The conserved short linker between CC1-CAD and IDstim facilitates the IDstim-mediated STIM1 inhibition. Our findings expand our understanding how the unintended activation of SOCE is prevented under resting conditions.