STIM proteins: dynamic calcium signal transducers

Abstract

Stromal interaction molecule (STIM) proteins are dynamic sensors of Ca²⁺ stored within the endoplasmic reticulum (ER) and are triggered by Ca²⁺ store depletion to self-activate, aggregate and translocate to discrete ER-plasma membrane junctional domains. There STIM proteins attach to the plasma membrane and tether and activate the highly Ca²⁺ selective Orai family of plasma membrane Ca²⁺ entry channels. The amino-terminal ER-luminal segments of STIM proteins are the Ca²⁺ sensing domains by virtue of specific EF-hand domain Ca²⁺ binding sites,which are highly tuned to detect small changes in luminal Ca²⁺ levels. The detection of decreased luminal Ca²⁺ concentrations triggers a conformational change that leads to aggregation and translocation of STIM proteins. Cytoplasmic carboxy-terminal STIM protein domains contain a uniquely configured group of α-helical sequences that form an activating domain able to bind to and gate the Orai channel in the plasma membrane. The helical domains can both mediate and regulate the Orai channel-coupling process. The STIM-induced ER-plasma membrane junctional domains contain a number of important regulatory proteins including CRAC regulatory protein 2A (CRACR2A), junctate, store-operated Ca²⁺ entry (SOCE)-associated regulatory factor (SARAF), golli and partner of STIM1 (POST). These proteins turn on and off the coupling between STIM proteins and the Ca²⁺ signalling target proteins that function within junctions. New information reveals STIM proteins as sensors not only of decreased ER Ca²⁺ but also of oxidative stress, temperature increases, hypoxic stress and acidosis. STIM proteins also target proteins other than Orai channels, including voltage-operated Ca_V1.2 channels, transient receptor potential channels (TRPCs) and plasma membrane Ca²⁺ ATPase (PMCA) and SERCA Ca²⁺ pumps. The function of STIM proteins is to generate long-term spatially discrete Ca²⁺ entry signals that specifically turn on transcriptional events. The triggered Ca²⁺ entry also replenishes stores, and this is required to maintain Ca²⁺ oscillations and to protect the integrity of the ER from potentially damaging decreases in ER Ca²⁺ levels that could compromise the protein trafficking and assembly functions of ER.