Figure 8.

Model for CRAC channel activity regulation by SARAF. (A) Under resting conditions, STIM1 and SARAF interact, the SOAR stabilizes STIM1 dimers, and intramolecular interactions with CC1 and ID maintain SOAR in the resting conformation. Upon Ca²⁺ depletion from the ER, STIM1 partially unfolds; yet, the formation of ER–PM contact sites and trapping of Orai1 and channel activation are transiently inhibited by the ID. Stimulatory interaction between SARAF and STIM1 relieves the ID inhibition and promotes interaction of STIM1 with PM lipids. Recruitment of additional SARAF molecules facilitates coupling activation between STIM1 and Orai1. (B) Channel activation at full strength leads to a rise in intracellular Ca²⁺ close to the channel that induces negative feedback through electrostatic interactions of Ca²⁺ with negatively charged residues within the ID. (C) Left: Both activation and SCDI are attenuated in the absence of SARAF. Right: Mutation of Ca²⁺ binding residues within the STIM1 ID eliminates SCDI.