STIMproteiner

STIMproteiner (STIM proteins) are a family of single-pass transmembrane proteins that function as calcium sensors in the endoplasmic reticulum (ER). The two main vertebrate homologs are STIM1 and STIM2. They monitor ER Ca2+ store levels through an EF-hand domain located in the ER lumen. When stores are full, Ca2+ binding maintains STIM in a resting state; depletion of ER Ca2+ induces conformational changes, oligomerization, and translocation to ER–plasma membrane junctions where STIM proteins interact with Orai calcium channels (Orai1/2/3) on the plasma membrane to activate store-operated calcium entry (SOCE). The resulting Ca2+ influx replenishes ER stores and sustains cytosolic Ca2+ signals.

STIM1 and STIM2 differ in their activation and roles. STIM1 responds to rapid and substantial Ca2+ loss and drives robust SOCE, while STIM2 has a higher Ca2+ affinity and can be activated by smaller decreases in ER Ca2+, contributing to basal or fine-tuned Ca2+ signaling. The cytosolic region contains coiled-coil domains that mediate oligomerization and direct interaction with Orai channels, enabling efficient coupling to SOCE.

Physiological functions of STIMproteiner are broad and include regulation of immune cell activation, muscle contraction, neuronal signaling, secretion, gene expression, and metabolism. Dysfunction of STIM1 or STIM2, or of the SOCE pathway, can lead to immune deficiencies, muscular disorders, or other Ca2+-related pathologies. Regulation occurs through alternative splicing, post-translational modifications, and interactions with regulatory factors such as SARAF and other SOCE components. STIM proteins are evolutionarily conserved across animals.