SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling

Store operated calcium entry (SOCE) is a principal cellular process by which cells regulate basal calcium, refill intracellular Ca²⁺ stores, and execute a wide range of specialized activities. STIM and Orai proteins have been identified as the essential components enabling the reconstitution of Ca²⁺ release-activated Ca²⁺ (CRAC) channels that mediate SOCE. Here, we report the molecular identification of SARAF as a negative regulator of SOCE. Using heterologous expression, RNAi-mediated silencing and site directed mutagenesis combined with electrophysiological, biochemical and imaging techniques we show that SARAF is an endoplasmic reticulum membrane resident protein that associates with STIM to facilitate slow Ca ²⁺-dependent inactivation of SOCE. SARAF plays a key role in shaping cytosolic Ca²⁺ signals and determining the content of the major intracellular Ca²⁺ stores, a role that is likely to be important in protecting cells from Ca²⁺ overfilling.