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‐ca...

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Published in:The Journal of physiology 2024-04, Vol.602 (8), p.1475-1507
Main Authors: Sallinger, Matthias, Grabmayr, Herwig, Humer, Christina, Bonhenry, Daniel, Romanin, Christoph, Schindl, Rainer, Derler, Isabella
Format: Article
Language:English
Subjects:
Alternative splicing
Calcium (intracellular)
Calcium - metabolism
Calcium channels
Calcium Release Activated Calcium Channels
Calcium Signaling - physiology
Calcium signalling
Channel opening
CRAC
EF‐hand
Endoplasmic reticulum
Membrane Proteins - metabolism
ORAI1 Protein
Proteins
Signal transduction
STIM1
STIM1 C‐terminus
Stromal Interaction Molecule 1 - metabolism
Stromal Interaction Molecules - metabolism
Transcription activation
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Summary: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. Figure 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.
ISSN:0022-3751
1469-7793
1469-7793
DOI:10.1113/JP283828