Activation mechanisms and structural dynamics of STIM proteins

The family of stromal interaction molecules (STIM) includes two widely expressed single-pass endoplasmic reticulum (ER) transmembrane proteins and additional splice variants that act as precise ER-luminal Ca²⁺ sensors. STIM proteins mainly function as one of the two essential components of the so-called Ca²⁺ release-activated Ca²⁺ (CRAC) channel. The second CRAC channel component is constituted by pore-forming Orai proteins in the plasma membrane. STIM and Orai physically interact with each other to enable CRAC channel opening, which is a critical prerequisite for various downstream signalling pathways such as gene transcription or proliferation. Their activation commonly requires the emptying of the intracellular ER Ca²⁺ store. Using their Ca²⁺ sensing capabilities, STIM proteins confer this Ca²⁺ content-dependent signal to Orai, thereby linking Ca²⁺ store depletion to CRAC channel opening. Here we review the conformational dynamics occurring along the entire STIM protein upon store depletion, involving the transition from the quiescent, compactly folded structure into an active, extended state, modulation by a variety of accessory components in the cell as well as the impairment of individual steps of the STIM activation cascade associated with disease.