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 (TM) proteins and additional splice variants that act as precise ER-luminal calcium (Ca 2+ ) sensors. STIM proteins mainly function as one of the two essential components of the so-called Ca 2+ release-activated Ca 2+ (CRAC) channel. The second CRAC channel component is constituted by pore-forming Orai proteins in the plasma membrane (PM). STIM and Orai physically interact with each other to enable CRAC channel opening, which is a critical prerequisite for various downstream signaling pathways such as gene transcription or proliferation. Their activation commonly requires the emptying of the intracellular ER Ca 2+ store. Using their Ca 2+ sensing capabilities, STIM proteins confer this Ca 2+ content dependent signal to Orai, thereby linking Ca 2+ 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, the 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. Abstract figure legend STIM activation involves a series of conformational rearrangements that transform the protein from a quiescent, tight state (left) into an active, extended state (right). While the exact series of events is still unresolved, currently available structural resolutions of STIM represent key pieces in solving the puzzle of STIM activation. Structural resolutions were derived from the Protein Data Bank (PDB) with the indicated identifiers. This article is protected by copyright. All rights reserved.