{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nORAI1 is a critical plasma membrane protein that functions as an essential component of the calcium‐release activated calcium (CRAC) channel, thereby mediating store‐operated calcium entry (SOCE) in immune cells. Initial studies demonstrated that upon receptor or antigen stimulation, depletion of endoplasmic reticulum Ca²⁺ triggers the redistribution of the Ca²⁺ sensor STIM1 to regions closely apposed to the plasma membrane, where STIM1 directly couples to ORAI1 to activate Ca²⁺ influx. These processes are indispensable for lymphocyte activation, gene transcription via NFAT, and normal immune responses; indeed, mutations in ORAI1 underlie severe combined immunodeficiency (SCID) in humans."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, ORAI1 is characterized by four transmembrane domains with key conserved acidic residues that form the ion‐selective pore of the CRAC channel. Detailed electrophysiological analyses have revealed that mutations in residues such as E106 and other key positions dramatically alter the Ca²⁺ selectivity and gating properties of the channel. In turn, interactions with STIM1, through its cytosolic activation domains, induce conformational rearrangements and multimerization of ORAI1 that are necessary for channel opening. Moreover, studies manipulating the stoichiometry and the structure of ORAI1 have provided evidence that its precise molecular architecture and dynamic coupling to STIM1 are crucial for finely tuned Ca²⁺ \nsignaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in immune cell activation, ORAI1 is emerging as a multifaceted regulator of Ca²⁺ signaling in diverse cell types. Its function extends to the regulation of endothelial Ca²⁺ dynamics, where it contributes to the maintenance of vascular integrity, as well as to the control of cell migration, proliferation, and apoptosis in cancer cells. Altered expression or gain‐of‐function mutations of ORAI1 have been implicated in pathological conditions such as tumor metastasis, where abnormal Ca²⁺ influx can promote invasive behavior, and in redox‐sensitive pathways that modulate cell survival. In addition, ORAI1 interacts with other channel proteins, including members of the TRPC family, to form heteromeric complexes that further diversify store‐operated and even store‐independent Ca²⁺ entry mechanisms. These studies not only underscore the centrality of ORAI1 in Ca²⁺ homeostasis but also suggest that modulation of its activity may offer novel therapeutic avenues in cancer and other diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "46"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stefan Feske, Yousang Gwack, Murali Prakriya, et al. 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