Abstract
Ca2+ entry into the cell via store-operated Ca2+ release-activated Ca2+ (CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca2+ channels open after depletion of intracellular Ca2+ stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca2+ sensor, while Orai forms a highly Ca2+-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca2+ permeation into the cell.
Highlights
CA2ϩ IS a major intracellular messenger in eukaryotic cells
The severe combined immune deficiency (SCID) syndrome, which is accompanied by a defect in Ca2ϩ release-activated Ca2ϩ (CRAC) channel function, cleared the way to the discovery of the Orai1 channel protein and its mutant Orai1 R91W, occurring in SCID patients [46]
The Orai channel is the plasma membrane (PM) pore-forming subunit of the CRAC channel [46, 84, 128, 170, 178, 181, 185, 186], which is made up of four transmembrane (TM) domains flanked by cytosolic NH2 and COOH termini [47, 60, 170] and forms highly Ca2ϩ-selective pores located in the PM
Summary
CA2ϩ IS a major intracellular messenger in eukaryotic cells. Changes in intracellular Ca2ϩ concentration are required for many physiological processes ranging from fast events like exocytosis to long-term processes like proliferation [13, 14, 74]. A recent crystal structure of a STIM1 COOH-terminal fragment (SOAR aa344 – 442), representing the minimal Orai activating fragment and including CC2 and CC3, has revealed four separate regions (Fig. 1A), i.e., S␣1 (aa345–391), S␣2 (aa393–398), S␣3 (aa400 – 403), and S␣4 (aa409 – 437) [180].
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