{"gene":"STIM1","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2009,"finding":"The STIM1 fragment 344-442 (SOAR, STIM1 Orai Activating Region) is both necessary and sufficient to fully activate all Orai channels; STIM1 residues 450-485 regulate the strength of STIM1-Orai1 interaction; the polybasic STIM1 domain (672-685) mediates inward rectification of Orai1 by interacting with a Pro-rich region in the Orai1 N-terminus; STIM1-Orai1 co-clustering is not sufficient for Orai1 activation; an intact C-terminal alpha-helical region of Orai is required for activation by SOAR.","method":"Truncation/deletion mutants, point mutagenesis, electrophysiology, co-clustering assays in HEK293 cells","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple mutagenesis constructs with functional electrophysiological readouts, replicated across multiple Orai isoforms in a single rigorous study","pmids":["19182790"],"is_preprint":false},{"year":2006,"finding":"The cytosolic C-terminus of STIM1 is sufficient to activate SOC, ICRAC, and TRPC1 channels even after endogenous STIM1 depletion; the ERM domain mediates selective binding of STIM1 to TRPC1, 2, and 4 (but not TRPC3, 6, or 7); the cationic lysine-rich region is essential for gating TRPC1; deletion of either region converts the constitutively active STIM1(D76A) into a dominant-negative that blocks native SOC, TRPC1, and ICRAC.","method":"Domain deletion constructs, siRNA knockdown, electrophysiology, co-immunoprecipitation, dominant-negative mutant analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with domain mutants, multiple orthogonal methods (electrophysiology, binding, siRNA rescue), multiple channel types tested","pmids":["16906149"],"is_preprint":false},{"year":2010,"finding":"STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress, which activates constitutive Ca2+ entry independent of intracellular Ca2+ store depletion; STIM1- and Orai1-deficient cells are resistant to oxidant stress-induced Ca2+ entry and cell death.","method":"S-glutathionylation assay, site-directed mutagenesis (C56), Ca2+ imaging, STIM1/Orai1 knockout/knockdown cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical identification of modification site with mutagenesis validation and functional Ca2+ entry readout in a single study","pmids":["20679432"],"is_preprint":false},{"year":2008,"finding":"STIM1 and Orai1 are recruited to the immunological synapse between T cells and dendritic cells, where Ca2+ influx is localized at the contact zone; expression of dominant-negative Orai1 blocked T cell Ca2+ signaling but did not prevent initial accumulation of STIM1, Orai1, and CD3 at the contact zone.","method":"Live fluorescence microscopy, intracellular Ca2+ imaging with EGTA, dominant-negative Orai1 expression, primary human T cell/dendritic cell conjugates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging with functional Ca2+ readout in primary cells, dominant-negative dissection of mechanism","pmids":["18250319"],"is_preprint":false},{"year":2008,"finding":"Store depletion triggers a STIM1-dependent conformational change in Orai1 (decrease in Orai1-Orai1 FRET) concurrent with a large increase in STIM1-Orai1 FRET, indicating direct physical interaction; Orai1 exists as a multimer in resting cells; the Orai1 conformational change requires STIM1 co-expression and is abrogated by Orai1 mutations that impair STIM1 interaction.","method":"Live-cell FRET microscopy, CFP/YFP-tagged STIM1 and Orai1 constructs, point mutagenesis of Orai1 STIM1-interaction sites","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — FRET-based structural dynamics with mutagenesis validation, multiple constructs tested in one rigorous study","pmids":["18832420"],"is_preprint":false},{"year":2008,"finding":"Reversal of STIM1 puncta formation (and thus SOCE termination) absolutely requires SOCE-dependent store refilling; ML-9 causes rapid, store-independent reversal of STIM1 puncta and inhibits SOCE and ICRAC; STIM1 puncta form at specific predetermined cellular loci; ML-9 effect is not mediated through MLCK inhibition.","method":"Live-cell fluorescence imaging of EYFP-STIM1, SOCE pharmacology, MLCK inhibitor comparisons, EF-hand constitutively active mutant","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence, multiple mutant and pharmacological controls, single lab","pmids":["18285445"],"is_preprint":false},{"year":2008,"finding":"STIM1 co-immunoprecipitates with TRPC1; STIM1 gates TRPC1 by electrostatic interaction between lysines K684 and K685 of the STIM1 polybasic domain and conserved negative charges (aspartates/glutamates) in TRPC channels; charge-swap mutants of STIM1(K684E,K685E) with TRPC1(D639E,D640E) restore channel activation.","method":"Co-immunoprecipitation, charge-swap mutagenesis, electrophysiology, siRNA knockdown","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1 / Strong — charge-swap mutagenesis with electrophysiological validation constitutes near-reconstitution level evidence for a specific gating mechanism","pmids":["17517433","19574740"],"is_preprint":false},{"year":2008,"finding":"STIM1 is present both in the ER and at the plasma membrane surface; the Ca2+-binding-defective STIM1(EF) mutant localizes exclusively in stable near-PM ER junctions and is not trafficked to the plasma membrane; surface STIM1(WT) plays a regulatory role in SOC activation as external anti-N-terminal STIM1 antibody blocked STIM1(EF)-mediated Ca2+ entry only in cells co-expressing endogenous STIM1(WT).","method":"Surface biotinylation, streptavidin pulldown, EF-hand mutagenesis (D76A/E87A), extracellular antibody application, Ca2+ imaging","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and functional antibody block, single lab, two orthogonal methods","pmids":["18635545"],"is_preprint":false},{"year":2000,"finding":"STIM1 protein is located at the cell surface of K562 cells (established by immunofluorescence and cell-surface biotinylation); STIM1 is phosphorylated predominantly on serine residues in vivo and undergoes N-linked glycosylation; STIM1 is not secreted and does not undergo proteolytic processing.","method":"Immunofluorescence, cell-surface biotinylation, phosphorylation analysis, western blot, specific antibodies","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical surface labeling and PTM characterization, single lab, two orthogonal methods","pmids":["11004585"],"is_preprint":false},{"year":2014,"finding":"STIM1 gain-of-function mutation R304W (in coiled-coil 1 domain) causes constitutive activation of the CRAC channel; platelets from patients show elevated resting Ca2+ levels and preactivated state; the coiled-coil 1 domain plays a role in keeping STIM1 inactive.","method":"Patient genetics, heterologous expression of STIM1 p.R304W, Ca2+ measurements in platelets, zebrafish model recapitulating bleeding phenotype","journal":"Proceedings of the National Academy of Sciences of the United States of America / Human mutation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — functional expression in two independent studies with patient and zebrafish validation, Ca2+ measurements confirm constitutive activation","pmids":["24591628","24619930"],"is_preprint":false},{"year":2015,"finding":"STIM1 dimers activate Orai1 through unimolecular coupling: introducing the F394H mutation in only one monomer of a SOAR concatemer-dimer has no effect on Orai1 binding or activation, whereas mutation in both monomers abolishes function; this argues against dimeric interaction between STIM1 and two adjacent Orai1 subunits.","method":"SOAR concatemer-dimer constructs with F394H point mutations, Orai1 binding assays, electrophysiology","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis of defined residues in engineered concatemer dimers with functional readout, single rigorous study","pmids":["26399906"],"is_preprint":false},{"year":2018,"finding":"The STIM1 luminal domain has 5–6 Ca2+-binding sites; Ca2+ binding at these sites is energetically coupled to the canonical EF-hand site; Ca2+ dissociation controls a switch to a second structured conformation rather than protein unfolding; mutations at the other luminal Ca2+-binding sites affect physiological STIM1 activation in cells.","method":"Biophysical Ca2+-binding measurements, NMR/structural analysis, mutagenesis of luminal domain, cell-based SOCE assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical reconstitution of Ca2+-binding coupled with mutagenesis and cell-based validation in one study","pmids":["30382093"],"is_preprint":false},{"year":2019,"finding":"Sequential Ca2+-dependent conformational changes of the luminal STIM1 domain upon activation were determined; Ca2+ dissociation destabilizes the two EF-hands, triggering disassembly of a hydrophobic cleft formed with the SAM domain; a single Ca2+ ion is sufficient to stabilize the luminal complex in MD simulations; point mutations in the canonical EF-hand and hydrophobic cleft (associated with tubular aggregate myopathy or cancer) yield constitutively clustered STIM1 and constitutive Orai1 activation.","method":"Molecular dynamics simulations, live-cell Ca2+ recordings, site-directed mutagenesis of EF-hand and hydrophobic cleft residues","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MD simulations combined with live-cell functional validation and disease-associated mutagenesis, multiple orthogonal methods","pmids":["31744929"],"is_preprint":false},{"year":2015,"finding":"STIM1 and Orai1 form nanoscale clusters at ER-PM junctions upon store depletion; STIM1 extended molecules bridge a ~12-nm ER-PM gap; Orai1 cluster into puncta on raised membrane subdomains; the stoichiometry of Orai1 channels is unchanged by store depletion or STIM1 co-expression; a portion of Orai1 channels are spaced ~15 nm apart, consistent with interaction with small STIM1 clusters.","method":"Transmission and freeze-fracture electron microscopy of STIM1/Orai1-expressing HEK293 cells, thapsigargin-induced store depletion, Monte Carlo analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct ultrastructural visualization by two EM methods with quantitative analysis, single rigorous study","pmids":["26351694"],"is_preprint":false},{"year":2017,"finding":"ER Ca2+ store depletion induces STIM1 phosphorylation at tyrosine 361 (Y361) via Pyk2 kinase; the phospho-defective Y361F mutant forms puncta but fails to recruit Orai1, preventing SOCE; in mouse lungs, Y361F expression prevented PAR1-induced vascular permeability increase.","method":"Site-directed mutagenesis (Y361F), phospho-specific detection, co-localization imaging, Pyk2 kinase identification, SOCE measurements, in vivo vascular permeability assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase identification with mutagenesis and in vivo functional validation, single lab","pmids":["28218251"],"is_preprint":false},{"year":2014,"finding":"STIM1 is transported by microtubule plus ends to the front of migrating endothelial leader cells; local ER Ca2+ depletion at the front activates STIM1; polarized STIM1 activity supports pulsatile front retraction and adhesion during directed cell migration.","method":"Live-cell fluorescence imaging of STIM1 and microtubule dynamics, STIM1 localization in migrating leader cells, Ca2+ imaging","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell localization tied to functional migration phenotype, single lab","pmids":["24463606"],"is_preprint":false},{"year":2011,"finding":"STIM1 concentration controls the magnitude of store-operated Ca2+ entry, and elevated STIM1 concentration activates a Ca2+-driven, PKC-δ- and RasGRP-dependent proapoptotic Erk signaling pathway in developing B cells; overexpression of STIM1 conferred a competitive disadvantage to developing B cells; this pathway is biochemically distinct from DAG-induced Erk activation.","method":"Genetic mouse models (PKC-δ KO, STIM1 overexpression), biochemical pathway analysis, epistasis with PKC-δ and RasGRP","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in multiple mouse models with biochemical pathway dissection, single lab","pmids":["21441934"],"is_preprint":false},{"year":2017,"finding":"Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 at a site adjacent to the STIM1-Orai1 coupling region; this interaction disrupts the STIM1-Orai1 complex and disassembles STIM1 oligomers, facilitating slow Ca2+-dependent inactivation of SOCE.","method":"Co-immunoprecipitation, CaM-binding site mapping by mutagenesis, SOCE/ICRAC measurements with wild-type and constitutively active STIM1 mutant, STIM1 oligomer analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding site identification by mutagenesis with functional SOCE/inactivation readout and oligomer disruption assay in a single rigorous study","pmids":["29051492"],"is_preprint":false},{"year":2019,"finding":"STIM1 helix α3 (residues 400-403) within SOAR/CAD does not mediate initial STIM1-Orai1 interaction but is essential for transmitting STIM1 binding into Orai1 channel gating; cysteine crosslinking revealed proximity of STIM1 α3 to Orai1 TM3, defining a STIM1-Orai1 gating interface (SOGI).","method":"Mutagenesis of STIM1 α3, cysteine crosslinking, co-immunoprecipitation, electrophysiology","journal":"Cell calcium","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crosslinking defines physical interface, mutagenesis dissects binding vs. gating, functional electrophysiology validation in one study","pmids":["30831274"],"is_preprint":false},{"year":2016,"finding":"STIM1 contains a cholesterol-binding domain located within the SOAR region; STIM1/SOAR associates functionally with cholesterol at the inner plasma membrane leaflet; cholesterol depletion causes SOAR detachment from the plasma membrane and enhances SOAR-Orai1 association.","method":"Protein-lipid interaction assays, fluorescence microscopy, cholesterol depletion, SOAR domain constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-lipid binding assay with functional consequence shown, single lab, two orthogonal methods","pmids":["27459950"],"is_preprint":false},{"year":2023,"finding":"STIM1 SOAR oligomerization promotes direct interaction with plasma membrane phosphoinositides to trap STIM1 at ER-PM contact sites; a cluster of conserved lysine residues within SOAR mediates this lipid interaction; the interaction is co-regulated by STIM1 coiled-coil 1 and inactivation domains.","method":"Electron and fluorescence microscopy, protein-lipid interaction assays, mutagenesis of SOAR lysine cluster","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein-lipid binding with structural imaging and mutagenesis, single lab","pmids":["36906853"],"is_preprint":false},{"year":2015,"finding":"Calsequestrin 1 (CSQ1) physically interacts with STIM1; increased monomeric CSQ1 enhances CSQ1-STIM1 interaction and reduces STIM1-Orai1 association and SOCE; C-terminal deletions in CSQ1 abolish its ability to modulate STIM1-Orai1 interaction.","method":"Co-immunoprecipitation, CSQ1 overexpression and deletion mutants, SOCE measurements in HEK293 cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with deletion mutant dissection and functional SOCE readout, single lab","pmids":["26087026"],"is_preprint":false},{"year":2012,"finding":"Surf4 associates with STIM1 in the ER (identified by affinity purification); deletion of Surf4 in DT40 B cells markedly increases SOCE and facilitates STIM1 clustering upon store depletion, indicating Surf4 is a negative modulator of STIM1-mediated SOCE.","method":"Affinity purification/mass spectrometry for binding partner identification, Surf4 knockout DT40 cells, SOCE measurements, STIM1 clustering assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner identified by affinity purification with functional KO validation, single lab","pmids":["22609200"],"is_preprint":false},{"year":2021,"finding":"Desmin (major skeletal muscle intermediate filament protein) interacts with the CC1-SOAR domains of STIM1; desmin-STIM1 interaction enhances STIM1 oligomerization yet limits SOCE; in desmin-KO mice, STIM1 retention at the Z-line is lost and SR Ca2+ refilling efficiency is altered.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization, desmin-KO mouse analysis, Ca2+ signaling measurements","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner identified by Y2H validated by co-IP and KO mouse with functional readout, single lab","pmids":["34494555"],"is_preprint":false},{"year":2022,"finding":"STIM1 constitutively maintains ER-PM peripheral coupling in contractile vascular smooth muscle cells (VSMCs) independent of ER Ca2+ store depletion; STIM1 KO in VSMCs reduces the number/size of SR-PM junctions, disrupts nanoscale colocalization of Ca2+-release sites with Ca2+-activated channels, diminishes channel activity, and causes hypotension and blunted arterial contractility.","method":"SMC-specific inducible STIM1 knockout mice, SR-PM junction imaging, nanoscale colocalization analysis, Ca2+ signaling, vascular contractility measurements","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal structural and functional readouts, in vivo physiological phenotype","pmids":["35147077"],"is_preprint":false},{"year":2021,"finding":"A neuronal splice variant STIM1B, containing an inserted domain B, shows exclusive neuronal expression, slower ER-PM cluster formation kinetics, slower ICRAC activation, and reduced inactivation compared to canonical STIM1; STIM1B targets to presynaptic sites via domain B and converts synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement at high-frequency stimulation.","method":"Cloning and characterization of STIM1B splice variant, ICRAC electrophysiology, live imaging of cluster formation, presynaptic targeting, synaptic plasticity recordings in primary neurons","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — novel isoform functionally characterized by electrophysiology, imaging, and synaptic physiology in primary neurons in a single rigorous study","pmids":["33730587"],"is_preprint":false},{"year":2008,"finding":"STIM1 deficiency in macrophages abolishes FcγR-induced Ca2+ entry and phagocytosis; STIM1-deficient mice are resistant to experimental immune thrombocytopenia, anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis, establishing STIM1 as an essential component of FcγR activation.","method":"STIM1 conditional knockout macrophages, Ca2+ imaging, phagocytosis assay, multiple in vivo disease models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple in vitro and in vivo functional readouts across several disease models","pmids":["18941110"],"is_preprint":false},{"year":2007,"finding":"STIM1 in the plasma membrane (constitutively surface-localized pool) regulates ARC (arachidonic acid-regulated Ca2+-selective) channels in a manner independent of store depletion, EF-hand Ca2+ binding, and STIM1 translocation to the plasma membrane; extracellular antibody targeting the N-terminal domain of STIM1 selectively inhibits ARC channel activity; mutations preventing N-glycosylation-dependent plasma membrane expression of STIM1 specifically inhibit ARC channels without affecting CRAC.","method":"Extracellular antibody inhibition, N-glycosylation mutants preventing PM expression, CRAC vs. ARC channel current recordings","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct antibody-block and glycosylation mutant approaches with separate channel current readouts, single lab","pmids":["17391754"],"is_preprint":false},{"year":2010,"finding":"STIM1 regulates TRPC6 expression at the plasma membrane, causing translocation of TRPC6 to the ER; STIM1-mediated TRPC6 internalization reduces TRPC6-TRPC1 and TRPC6-TRPC3 heteromultimerization; TRPC6 expression in the ER increases passive Ca2+ efflux and basal cytosolic Ca2+.","method":"Co-immunoprecipitation, subcellular fractionation, TRPC6 localization imaging, Ca2+ measurements","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and localization with functional Ca2+ readout, single lab, two orthogonal methods","pmids":["25088676"],"is_preprint":false},{"year":2014,"finding":"STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by facilitating invadopodium precursor assembly via Src activation; Orai1 blockade inhibits MT1-MMP recycling to the plasma membrane and entraps MT1-MMP in endocytic compartments, inhibiting ECM degradation; STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft model.","method":"Ca2+ imaging, STIM1/Orai1 knockdown, invadopodium assembly assays, MT1-MMP trafficking assays, xenograft mouse model","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway placement with trafficking assay and in vivo xenograft, single lab","pmids":["25404747"],"is_preprint":false},{"year":2022,"finding":"ER-resident STIM1/2 physically interacts with pannexin-1 (Panx1) at a hydrophobic region within the Panx1 N-terminus; STIM recruitment couples Ca2+ entry via NMDARs to large-pore Panx1 activation; a Panx1 N-terminus-recognizing antibody blocks large-pore activation by STIM1/2.","method":"Co-immunoprecipitation, interaction interface mapping with Panx1 deletion mutants, function-blocking antibody, Ca2+ entry assays in neurons","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding interface mapped by deletion mutagenesis with functional antibody-block and KO neuron validation, single lab","pmids":["36037373"],"is_preprint":false},{"year":2019,"finding":"STIM1 phosphorylation at Y316 positively regulates STIM1-Orai1 colocalization and SOCE/ICRAC; the phospho-defective Y316F mutant reduces STIM1 tyrosine phosphorylation, SOCE, and ICRAC; Y316F alters STIM1-SARAF interaction under both resting and Ca2+-store-depleted conditions and enhances slow Ca2+-dependent inactivation.","method":"Y316F mutagenesis, STIM1-Orai1 colocalization imaging, SOCE and ICRAC measurements, STIM1-SARAF co-immunoprecipitation, SARAF knockdown epistasis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts and epistasis with SARAF, single lab","pmids":["30975919"],"is_preprint":false},{"year":2014,"finding":"STIM1 promotes cell migration in vascular smooth muscle cells (VSMCs); STIM1 interacts with TRPC1 in VSMCs; extracellular antibody against the N-terminal STIM1 domain inhibits store-depletion-evoked Ca2+ current and cell migration but not proliferation; plasma-membrane-localized STIM1 contributes to TRPC1-independent store-operated cationic current and migration.","method":"STIM1 siRNA, extracellular antibody application, Ca2+ entry and current measurements, migration assays, co-immunoprecipitation","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct antibody-block of surface STIM1 with migration and current readouts, co-IP for binding, single lab","pmids":["18802022"],"is_preprint":false},{"year":2023,"finding":"TSPAN18 directly interacts with STIM1 and competitively inhibits TRIM32-mediated ubiquitination and degradation of STIM1, thereby increasing STIM1 protein stability and SOCE-dependent Ca2+ influx.","method":"LC-MS/MS identification of TSPAN18, co-immunoprecipitation, TRIM32 ubiquitination assay, STIM1 stability measurements","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding and competitive ubiquitination mechanism identified by co-IP and functional assay, single lab","pmids":["37542345"],"is_preprint":false},{"year":2014,"finding":"ERK1/2-mediated phosphorylation of STIM1 at Ser575, Ser608, and Ser621 is triggered by EGF/H-Ras signaling and promotes STIM1 dissociation from EB1 (microtubule plus-end regulator); phospho-defective Ser-to-Ala mutations impair EGF-triggered cell migration while phosphomimetic mutations restore it; STIM1 phosphorylation is upstream of Ca2+ entry activation.","method":"Site-directed mutagenesis (S575A/S608A/S621A and S575E/S608E/S621E), ERK1/2 inhibition, STIM1-EB1 co-immunoprecipitation, migration assays, EMT marker analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site mutagenesis with functional migration readout and upstream kinase identification, single lab","pmids":["25447552"],"is_preprint":false},{"year":2017,"finding":"STIM1 ablation in dendritic cells impairs antigen cross-presentation and chemotaxis in vivo and in vitro; STIM1 deficiency disrupts phagosomal proteolysis, leucyl aminopeptidase activity, IRAP recruitment, and phagosome-endolysosome fusion without affecting phagosomal pH or ROS production; STIM1-dependent Ca2+ signaling promotes delivery of endolysosomal enzymes to phagosomes.","method":"Stim1 conditional KO in myeloid cells, cross-presentation assay, chemotaxis assay, phagosomal pH and ROS measurements, phagosome-endolysosome fusion assay, IRAP localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple mechanistic readouts in vivo and in vitro identifying a specific phagosomal trafficking function","pmids":["29176619"],"is_preprint":false},{"year":2020,"finding":"STIM1 stabilizes Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway during HCC tumor growth; downregulated STIM1 in metastatic HCC cells shifts metabolism from glycolysis toward AMPK-activated fatty acid oxidation (FAO), promoting anoikis-resistance and metastasis driven by Snail1; Snail1 suppresses STIM1/SOCE during metastasis creating a feedback loop.","method":"CRISPR-Cas9 STIM1 KO, lentiviral overexpression, Seahorse metabolic analysis, in vivo lung metastasis model, pathway (CaMKII/AKT/GSK-3β) analysis","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with metabolic and signaling pathway mechanistic readouts and in vivo validation, single lab","pmids":["32483465"],"is_preprint":false}],"current_model":"STIM1 is an ER-resident single-pass transmembrane Ca2+ sensor that, upon ER Ca2+ depletion, undergoes conformational changes (initiated by Ca2+ dissociation from its luminal EF-hand and other luminal Ca2+-binding sites, causing SAM-domain hydrophobic-cleft disassembly) leading to STIM1 oligomerization and translocation to ER-PM junctions, where its SOAR/CAD domain (residues 344-442) directly gates Orai1 channels via a unimolecular coupling mechanism and its polybasic domain (K684/K685) electrostatically gates TRPC1/4 channels; STIM1 activity is modulated by S-glutathionylation at C56 (oxidant activation), phosphorylation at Y361 by Pyk2 (required for Orai1 recruitment), phosphorylation at ERK1/2-target serines (promotes migration), phosphorylation at Y316 (regulates SARAF interaction and inactivation), and TRIM32-mediated ubiquitination (degradation opposed by TSPAN18); Ca2+-bound calmodulin binds activated STIM1 to disrupt STIM1-Orai1 complexes and STIM1 oligomers for slow inactivation; a plasma-membrane pool of STIM1 constitutively regulates ARC channels and platelet function; in contractile VSMCs STIM1 constitutively maintains SR-PM peripheral coupling independent of store depletion; a neuronal splice variant STIM1B targets to presynaptic sites to confer short-term synaptic enhancement; and STIM1-dependent SOCE controls diverse physiological processes including T-cell activation at the immunological synapse, dendritic-cell cross-presentation, FcγR-mediated phagocytosis, B-cell negative selection, invadopodium-driven cancer invasion, and enamel mineralization."},"narrative":{"mechanistic_narrative":"STIM1 is an ER-resident single-pass transmembrane Ca2+ sensor that couples depletion of ER Ca2+ stores to activation of plasma-membrane Ca2+ channels, driving store-operated Ca2+ entry (SOCE) across diverse physiological settings [PMID:16906149, PMID:30382093]. Sensing operates through the luminal domain, which carries the canonical EF-hand plus several additional energetically coupled Ca2+-binding sites; Ca2+ dissociation destabilizes the EF-hands and triggers disassembly of a hydrophobic cleft formed with the SAM domain, switching the protein into an activated conformation rather than unfolding it [PMID:30382093, PMID:31744929]. Disease- and cancer-associated mutations in the EF-hand or hydrophobic cleft, and a gain-of-function mutation in coiled-coil 1 (R304W) that causes a platelet bleeding disorder, lock STIM1 into a constitutively clustered, channel-activating state [PMID:24591628, PMID:24619930, PMID:31744929]. Activated STIM1 oligomerizes and is trapped at ER-PM junctions through SOAR-domain interactions with plasma-membrane phosphoinositides and cholesterol, bridging a ~12-nm ER-PM gap to form nanoscale clusters with its target channels [PMID:26351694, PMID:27459950, PMID:36906853]. The SOAR/CAD region (residues 344-442) is necessary and sufficient to gate Orai channels, with helix α3 transmitting binding into channel opening at a defined STIM1-Orai1 gating interface, operating through a unimolecular coupling mechanism [PMID:19182790, PMID:26399906, PMID:30831274]. Beyond Orai, the polybasic lysine-rich domain electrostatically gates TRPC1/4 channels [PMID:16906149, PMID:17517433, PMID:19574740]. STIM1 activity is tuned by phosphorylation (Pyk2 at Y361 for Orai1 recruitment, Y316 regulating SARAF interaction and inactivation, ERK1/2 serines promoting migration), by S-glutathionylation at C56 conferring oxidant-activated Ca2+ entry, by Ca2+-calmodulin-mediated complex disassembly driving slow inactivation, and by TRIM32-mediated ubiquitination opposed by TSPAN18 [PMID:20679432, PMID:28218251, PMID:29051492, PMID:30975919, PMID:37542345, PMID:25447552]. Through these mechanisms STIM1-dependent Ca2+ signaling controls T-cell and FcγR immune responses, dendritic-cell cross-presentation, directed cell migration and cancer invasion, vascular smooth-muscle coupling, and, via the neuronal splice variant STIM1B, presynaptic short-term synaptic enhancement [PMID:18250319, PMID:24463606, PMID:35147077, PMID:33730587, PMID:18941110, PMID:29176619].","teleology":[{"year":2000,"claim":"Before its Ca2+-sensing role was known, STIM1 was characterized biochemically as a phosphorylated, N-glycosylated, cell-surface-localized protein, establishing the basic protein chemistry and a surface pool later revisited functionally.","evidence":"Immunofluorescence, surface biotinylation, and PTM analysis in K562 cells","pmids":["11004585"],"confidence":"Medium","gaps":["No link to Ca2+ signaling established at this stage","Relative size of surface vs ER pool not quantified","Function of glycosylation/phosphorylation not addressed"]},{"year":2006,"claim":"Established that the cytosolic STIM1 C-terminus is sufficient to activate SOC, ICRAC, and TRPC1 channels, and mapped distinct domains (ERM for TRPC binding, lysine-rich region for TRPC1 gating), defining STIM1 as a multi-channel activator.","evidence":"Domain deletion constructs, siRNA, electrophysiology, co-IP, dominant-negative analysis","pmids":["16906149"],"confidence":"High","gaps":["Did not resolve the Orai-activating subregion within the C-terminus","Mechanism of luminal Ca2+ sensing not addressed","Direct vs indirect TRPC gating not distinguished"]},{"year":2007,"claim":"Demonstrated a store-independent function for the plasma-membrane STIM1 pool in gating ARC channels, distinguishing it from the ER store-operated mechanism.","evidence":"Extracellular antibody block, N-glycosylation mutants, CRAC vs ARC current recordings","pmids":["17391754"],"confidence":"Medium","gaps":["Molecular interface with ARC channels not mapped","Physiological contexts for surface STIM1 not defined here","Single-lab observation"]},{"year":2008,"claim":"Resolved the physical coupling logic of activation: store depletion drives direct STIM1-Orai1 interaction with an Orai1 conformational change, STIM1 puncta form at predetermined ER-PM loci, and electrostatic charge-swap experiments defined the polybasic-domain mechanism gating TRPC1.","evidence":"Live-cell FRET, EYFP-STIM1 imaging, charge-swap mutagenesis, SOCE pharmacology","pmids":["18832420","18285445","17517433","19574740","18635545"],"confidence":"High","gaps":["Atomic structure of the STIM1-Orai1 interface unresolved","Identity of factors defining puncta loci unknown","Stoichiometry of coupling not yet determined"]},{"year":2008,"claim":"Placed STIM1 in immune effector physiology, showing recruitment to the immunological synapse and an essential role in FcγR-mediated Ca2+ entry, phagocytosis, and multiple antibody-driven disease models.","evidence":"Live imaging of T-cell/DC conjugates, conditional KO macrophages, in vivo disease models","pmids":["18250319","18941110"],"confidence":"High","gaps":["Downstream Ca2+-dependent effectors not fully dissected","Cell-type-specific channel partners not defined","Initial synapse accumulation mechanism (Orai-independent) unexplained"]},{"year":2009,"claim":"Defined the minimal Orai-activating module SOAR (344-442) as necessary and sufficient to gate all Orai isoforms and showed co-clustering alone is insufficient, separating recruitment from gating.","evidence":"Truncation/point mutagenesis, electrophysiology, co-clustering assays in HEK293","pmids":["19182790"],"confidence":"High","gaps":["Residues transmitting binding into gating not yet pinpointed","Conformational basis of SOAR activation unresolved","Structural model of the coupled complex absent"]},{"year":2011,"claim":"Showed that STIM1 abundance is a tunable signaling variable, where elevated STIM1 engages a proapoptotic PKC-δ/RasGRP/Erk pathway in B-cell negative selection distinct from DAG-driven Erk.","evidence":"Genetic mouse models and biochemical epistasis","pmids":["21441934"],"confidence":"Medium","gaps":["Direct link between SOCE magnitude and Erk activation not biochemically reconstituted","Generalizability beyond developing B cells unclear","Single-lab finding"]},{"year":2014,"claim":"Connected STIM1 to directed migration and metastasis: microtubule plus-end transport polarizes STIM1 to the migrating front, ERK1/2 phosphorylation at S575/S608/S621 controls EB1 dissociation and migration, and STIM1/Orai1 Ca2+ oscillations drive invadopodium-mediated invasion.","evidence":"Live imaging, phospho-site mutagenesis, invadopodium/MT1-MMP trafficking assays, xenograft models","pmids":["24463606","25447552","25404747","18802022"],"confidence":"Medium","gaps":["Hierarchy between trafficking, phosphorylation, and Ca2+ entry not fully ordered","Direct kinase-substrate verification limited","In vivo relevance of EB1 dissociation not established"]},{"year":2014,"claim":"Identified STIM1 R304W in coiled-coil 1 as a human gain-of-function mutation causing constitutive CRAC activation and a platelet bleeding/preactivation phenotype, demonstrating CC1 maintains the resting state.","evidence":"Patient genetics, heterologous expression, platelet Ca2+ measurements, zebrafish model","pmids":["24591628","24619930"],"confidence":"High","gaps":["Structural mechanism by which CC1 enforces autoinhibition not resolved","Full spectrum of clinical manifestations not delineated","Relationship to tubular aggregate myopathy mutations not addressed here"]},{"year":2015,"claim":"Provided structural and mechanistic refinement of activation: ultrastructural imaging showed STIM1 bridges a ~12-nm ER-PM gap forming nanoscale Orai1 clusters, and concatemer-dimer mutagenesis established a unimolecular STIM1-Orai1 coupling mechanism.","evidence":"EM and freeze-fracture imaging, SOAR F394H concatemer dimers, electrophysiology","pmids":["26351694","26399906"],"confidence":"High","gaps":["Exact stoichiometry of STIM1 per Orai1 hexamer not fixed","Dynamics of cluster assembly not captured","Lipid contribution to junction formation not yet defined"]},{"year":2015,"claim":"Identified luminal/ER modulators CSQ1 and Surf4 as negative regulators that limit STIM1-Orai1 association and clustering, adding upstream brakes on SOCE.","evidence":"Co-IP, deletion mutants, KO cells, SOCE measurements","pmids":["26087026","22609200"],"confidence":"Medium","gaps":["Physiological settings where these brakes dominate unclear","Direct vs indirect modulation not fully separated","Single-lab findings"]},{"year":2016,"claim":"Showed SOAR contains a cholesterol-binding domain and that membrane lipid composition governs SOAR-PM attachment and SOAR-Orai1 association, introducing lipid regulation of coupling.","evidence":"Protein-lipid assays, cholesterol depletion, SOAR constructs","pmids":["27459950"],"confidence":"Medium","gaps":["In vivo relevance of cholesterol regulation untested","Interplay with phosphoinositide binding not resolved here","Single-lab finding"]},{"year":2017,"claim":"Defined regulatory inputs controlling activation and inactivation: Pyk2 phosphorylation at Y361 is required for Orai1 recruitment, and Ca2+-calmodulin binding adjacent to the coupling region disassembles STIM1-Orai1 complexes and oligomers for slow inactivation.","evidence":"Mutagenesis, phospho-detection, CaM-binding mapping, SOCE/inactivation assays, in vivo vascular permeability","pmids":["28218251","29051492"],"confidence":"High","gaps":["Spatiotemporal coordination of Y361 phosphorylation with clustering unclear","CaM-binding site structure not solved","Crosstalk between these regulatory layers unmapped"]},{"year":2017,"claim":"Defined a specific intracellular trafficking function of STIM1 in dendritic cells, showing Ca2+ signaling promotes endolysosomal enzyme delivery and phagosome-endolysosome fusion required for cross-presentation, independent of phagosomal pH and ROS.","evidence":"Myeloid conditional KO, cross-presentation, chemotaxis, phagosome fusion and IRAP assays","pmids":["29176619"],"confidence":"High","gaps":["Direct Ca2+ targets controlling fusion not identified","Channel partner in dendritic cells not specified here","Link between chemotaxis and trafficking defects not separated"]},{"year":2018,"claim":"Established the luminal sensing mechanism in molecular detail, demonstrating 5-6 Ca2+-binding sites energetically coupled to the canonical EF-hand and that Ca2+ loss drives a conformational switch rather than unfolding.","evidence":"Biophysical Ca2+-binding, structural analysis, mutagenesis, cell SOCE assays","pmids":["30382093"],"confidence":"High","gaps":["Full atomic structure of the activated luminal state incomplete","How luminal switch propagates to cytosolic SOAR not resolved here","Quantitative Ca2+ thresholds in cells not fixed"]},{"year":2019,"claim":"Refined activation mechanics: MD plus live-cell work resolved sequential luminal conformational changes, helix α3 (400-403) was shown to transmit binding into Orai1 gating at a defined gating interface (SOGI), and Y316 phosphorylation was tied to SARAF interaction and inactivation.","evidence":"MD simulations, cysteine crosslinking, mutagenesis, electrophysiology, co-IP","pmids":["31744929","30831274","30975919"],"confidence":"High","gaps":["High-resolution structure of the gated STIM1-Orai1 interface still absent","Kinase responsible for Y316 not identified here","Integration of α3 gating with luminal switch not mechanistically continuous"]},{"year":2021,"claim":"Expanded the partner and tissue repertoire: desmin retains STIM1 at the skeletal-muscle Z-line and modulates SOCE, and a neuronal splice variant STIM1B targets presynaptic sites to convert synaptic depression into Ca2+/Orai-dependent short-term enhancement.","evidence":"Y2H, co-IP, KO mouse, splice-variant cloning, ICRAC and synaptic plasticity recordings","pmids":["34494555","33730587"],"confidence":"High","gaps":["Mechanism by which STIM1B insertion alters kinetics not structurally defined","Desmin-STIM1 interface not mapped at residue level","Generality of STIM1B function across synapse types unknown"]},{"year":2022,"claim":"Demonstrated a store-depletion-independent constitutive role for STIM1 in maintaining ER-PM peripheral coupling in contractile vascular smooth muscle and a novel ER-STIM/pannexin-1 coupling mechanism in neurons.","evidence":"SMC-specific inducible KO with junction imaging and contractility; Panx1 interface mapping with function-blocking antibody","pmids":["35147077","36037373"],"confidence":"High","gaps":["Molecular determinants of constitutive coupling vs store-operated mode not separated","Panx1-STIM physiological output beyond Ca2+ entry unclear","Conservation across smooth-muscle beds untested"]},{"year":2023,"claim":"Identified protein-stability and lipid-trapping control of STIM1: SOAR oligomerization engages PM phosphoinositides to trap STIM1 at ER-PM contacts, and TSPAN18 competitively blocks TRIM32-mediated ubiquitination to stabilize STIM1 and boost SOCE.","evidence":"EM/fluorescence imaging, protein-lipid assays, LC-MS/MS, co-IP, ubiquitination and stability assays","pmids":["36906853","37542345"],"confidence":"Medium","gaps":["Triggers controlling TRIM32 vs TSPAN18 balance in vivo unclear","Coordination of phosphoinositide and cholesterol binding unresolved","Single-lab mechanistic claims"]},{"year":null,"claim":"How the discrete regulatory layers (luminal Ca2+ switch, phosphorylation, glutathionylation, CaM/SARAF inactivation, lipid trapping, and ubiquitin-mediated turnover) are integrated in time and space to produce graded, tissue-specific SOCE remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the activated full-length STIM1-Orai1 complex","Quantitative model linking regulatory inputs to channel output absent","Mechanistic basis for switching between store-operated and constitutive coupling modes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[11,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,18,27]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[19,20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,11,12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,13,24]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,27,32]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[13,20,24]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,26,35]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,11,13]}],"complexes":["STIM1-Orai1 CRAC channel complex"],"partners":["ORAI1","TRPC1","CALM1","SARAF","TSPAN18","TRIM32","DES","PANX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13586","full_name":"Stromal interaction molecule 1","aliases":[],"length_aa":685,"mass_kda":77.4,"function":"Acts as a Ca(2+) sensor that gates two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels (PubMed:15866891, PubMed:16005298, PubMed:16208375, PubMed:16537481, PubMed:16733527, PubMed:16766533, PubMed:16807233, PubMed:18854159, PubMed:19182790, PubMed:19249086, PubMed:19622606, PubMed:19706554, PubMed:22464749, PubMed:24069340, PubMed:24351972, PubMed:24591628, PubMed:25326555, PubMed:26322679, PubMed:28219928, PubMed:32415068). Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates CRAC channel pore-forming subunits ORA1, ORA2 and ORAI3 to generate sustained and oscillatory Ca(2+) entry (PubMed:16208375, PubMed:16537481, PubMed:32415068). Involved in enamel formation (PubMed:24621671)","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane; Cytoplasm, cytoskeleton; Sarcoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q13586/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STIM1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000167323","cell_line_id":"CID000355","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"STIM2","stoichiometry":10.0},{"gene":"BAG4","stoichiometry":0.2},{"gene":"BNIP1","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"MAPRE1","stoichiometry":0.2},{"gene":"AHSA1","stoichiometry":0.2},{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"HSPA14","stoichiometry":0.2},{"gene":"STX18","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000355","total_profiled":1310},"omim":[{"mim_id":"620181","title":"GRAM DOMAIN-CONTAINING PROTEIN 2A; GRAMD2A","url":"https://www.omim.org/entry/620181"},{"mim_id":"619863","title":"JUNCTOPHILIN 4; JPH4","url":"https://www.omim.org/entry/619863"},{"mim_id":"617189","title":"TRANSMEMBRANE PROTEIN 110; TMEM110","url":"https://www.omim.org/entry/617189"},{"mim_id":"617167","title":"SOLUTE CARRIER FAMILY 35, MEMBER G1; SLC35G1","url":"https://www.omim.org/entry/617167"},{"mim_id":"616670","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 1; ESYT1","url":"https://www.omim.org/entry/616670"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/STIM1"},"hgnc":{"alias_symbol":["GOK","D11S4896E"],"prev_symbol":[]},"alphafold":{"accession":"Q13586","domains":[{"cath_id":"1.10.150.50","chopping":"43-209","consensus_level":"medium","plddt":84.312,"start":43,"end":209},{"cath_id":"1.10.287.3550","chopping":"344-459","consensus_level":"high","plddt":88.6585,"start":344,"end":459},{"cath_id":"1.20.5","chopping":"210-264","consensus_level":"medium","plddt":79.6427,"start":210,"end":264},{"cath_id":"1.20.5","chopping":"280-340","consensus_level":"medium","plddt":83.2921,"start":280,"end":340}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13586","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13586-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13586-F1-predicted_aligned_error_v6.png","plddt_mean":67.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STIM1","jax_strain_url":"https://www.jax.org/strain/search?query=STIM1"},"sequence":{"accession":"Q13586","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13586.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13586/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13586"}},"corpus_meta":[{"pmid":"19182790","id":"PMC_19182790","title":"SOAR 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STIM1 residues 450-485 regulate the strength of STIM1-Orai1 interaction; the polybasic STIM1 domain (672-685) mediates inward rectification of Orai1 by interacting with a Pro-rich region in the Orai1 N-terminus; STIM1-Orai1 co-clustering is not sufficient for Orai1 activation; an intact C-terminal alpha-helical region of Orai is required for activation by SOAR.\",\n      \"method\": \"Truncation/deletion mutants, point mutagenesis, electrophysiology, co-clustering assays in HEK293 cells\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple mutagenesis constructs with functional electrophysiological readouts, replicated across multiple Orai isoforms in a single rigorous study\",\n      \"pmids\": [\"19182790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The cytosolic C-terminus of STIM1 is sufficient to activate SOC, ICRAC, and TRPC1 channels even after endogenous STIM1 depletion; the ERM domain mediates selective binding of STIM1 to TRPC1, 2, and 4 (but not TRPC3, 6, or 7); the cationic lysine-rich region is essential for gating TRPC1; deletion of either region converts the constitutively active STIM1(D76A) into a dominant-negative that blocks native SOC, TRPC1, and ICRAC.\",\n      \"method\": \"Domain deletion constructs, siRNA knockdown, electrophysiology, co-immunoprecipitation, dominant-negative mutant analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with domain mutants, multiple orthogonal methods (electrophysiology, binding, siRNA rescue), multiple channel types tested\",\n      \"pmids\": [\"16906149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress, which activates constitutive Ca2+ entry independent of intracellular Ca2+ store depletion; STIM1- and Orai1-deficient cells are resistant to oxidant stress-induced Ca2+ entry and cell death.\",\n      \"method\": \"S-glutathionylation assay, site-directed mutagenesis (C56), Ca2+ imaging, STIM1/Orai1 knockout/knockdown cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical identification of modification site with mutagenesis validation and functional Ca2+ entry readout in a single study\",\n      \"pmids\": [\"20679432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 and Orai1 are recruited to the immunological synapse between T cells and dendritic cells, where Ca2+ influx is localized at the contact zone; expression of dominant-negative Orai1 blocked T cell Ca2+ signaling but did not prevent initial accumulation of STIM1, Orai1, and CD3 at the contact zone.\",\n      \"method\": \"Live fluorescence microscopy, intracellular Ca2+ imaging with EGTA, dominant-negative Orai1 expression, primary human T cell/dendritic cell conjugates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging with functional Ca2+ readout in primary cells, dominant-negative dissection of mechanism\",\n      \"pmids\": [\"18250319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Store depletion triggers a STIM1-dependent conformational change in Orai1 (decrease in Orai1-Orai1 FRET) concurrent with a large increase in STIM1-Orai1 FRET, indicating direct physical interaction; Orai1 exists as a multimer in resting cells; the Orai1 conformational change requires STIM1 co-expression and is abrogated by Orai1 mutations that impair STIM1 interaction.\",\n      \"method\": \"Live-cell FRET microscopy, CFP/YFP-tagged STIM1 and Orai1 constructs, point mutagenesis of Orai1 STIM1-interaction sites\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — FRET-based structural dynamics with mutagenesis validation, multiple constructs tested in one rigorous study\",\n      \"pmids\": [\"18832420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Reversal of STIM1 puncta formation (and thus SOCE termination) absolutely requires SOCE-dependent store refilling; ML-9 causes rapid, store-independent reversal of STIM1 puncta and inhibits SOCE and ICRAC; STIM1 puncta form at specific predetermined cellular loci; ML-9 effect is not mediated through MLCK inhibition.\",\n      \"method\": \"Live-cell fluorescence imaging of EYFP-STIM1, SOCE pharmacology, MLCK inhibitor comparisons, EF-hand constitutively active mutant\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence, multiple mutant and pharmacological controls, single lab\",\n      \"pmids\": [\"18285445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 co-immunoprecipitates with TRPC1; STIM1 gates TRPC1 by electrostatic interaction between lysines K684 and K685 of the STIM1 polybasic domain and conserved negative charges (aspartates/glutamates) in TRPC channels; charge-swap mutants of STIM1(K684E,K685E) with TRPC1(D639E,D640E) restore channel activation.\",\n      \"method\": \"Co-immunoprecipitation, charge-swap mutagenesis, electrophysiology, siRNA knockdown\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — charge-swap mutagenesis with electrophysiological validation constitutes near-reconstitution level evidence for a specific gating mechanism\",\n      \"pmids\": [\"17517433\", \"19574740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 is present both in the ER and at the plasma membrane surface; the Ca2+-binding-defective STIM1(EF) mutant localizes exclusively in stable near-PM ER junctions and is not trafficked to the plasma membrane; surface STIM1(WT) plays a regulatory role in SOC activation as external anti-N-terminal STIM1 antibody blocked STIM1(EF)-mediated Ca2+ entry only in cells co-expressing endogenous STIM1(WT).\",\n      \"method\": \"Surface biotinylation, streptavidin pulldown, EF-hand mutagenesis (D76A/E87A), extracellular antibody application, Ca2+ imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and functional antibody block, single lab, two orthogonal methods\",\n      \"pmids\": [\"18635545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"STIM1 protein is located at the cell surface of K562 cells (established by immunofluorescence and cell-surface biotinylation); STIM1 is phosphorylated predominantly on serine residues in vivo and undergoes N-linked glycosylation; STIM1 is not secreted and does not undergo proteolytic processing.\",\n      \"method\": \"Immunofluorescence, cell-surface biotinylation, phosphorylation analysis, western blot, specific antibodies\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical surface labeling and PTM characterization, single lab, two orthogonal methods\",\n      \"pmids\": [\"11004585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIM1 gain-of-function mutation R304W (in coiled-coil 1 domain) causes constitutive activation of the CRAC channel; platelets from patients show elevated resting Ca2+ levels and preactivated state; the coiled-coil 1 domain plays a role in keeping STIM1 inactive.\",\n      \"method\": \"Patient genetics, heterologous expression of STIM1 p.R304W, Ca2+ measurements in platelets, zebrafish model recapitulating bleeding phenotype\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America / Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — functional expression in two independent studies with patient and zebrafish validation, Ca2+ measurements confirm constitutive activation\",\n      \"pmids\": [\"24591628\", \"24619930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIM1 dimers activate Orai1 through unimolecular coupling: introducing the F394H mutation in only one monomer of a SOAR concatemer-dimer has no effect on Orai1 binding or activation, whereas mutation in both monomers abolishes function; this argues against dimeric interaction between STIM1 and two adjacent Orai1 subunits.\",\n      \"method\": \"SOAR concatemer-dimer constructs with F394H point mutations, Orai1 binding assays, electrophysiology\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis of defined residues in engineered concatemer dimers with functional readout, single rigorous study\",\n      \"pmids\": [\"26399906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The STIM1 luminal domain has 5–6 Ca2+-binding sites; Ca2+ binding at these sites is energetically coupled to the canonical EF-hand site; Ca2+ dissociation controls a switch to a second structured conformation rather than protein unfolding; mutations at the other luminal Ca2+-binding sites affect physiological STIM1 activation in cells.\",\n      \"method\": \"Biophysical Ca2+-binding measurements, NMR/structural analysis, mutagenesis of luminal domain, cell-based SOCE assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical reconstitution of Ca2+-binding coupled with mutagenesis and cell-based validation in one study\",\n      \"pmids\": [\"30382093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sequential Ca2+-dependent conformational changes of the luminal STIM1 domain upon activation were determined; Ca2+ dissociation destabilizes the two EF-hands, triggering disassembly of a hydrophobic cleft formed with the SAM domain; a single Ca2+ ion is sufficient to stabilize the luminal complex in MD simulations; point mutations in the canonical EF-hand and hydrophobic cleft (associated with tubular aggregate myopathy or cancer) yield constitutively clustered STIM1 and constitutive Orai1 activation.\",\n      \"method\": \"Molecular dynamics simulations, live-cell Ca2+ recordings, site-directed mutagenesis of EF-hand and hydrophobic cleft residues\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MD simulations combined with live-cell functional validation and disease-associated mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"31744929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STIM1 and Orai1 form nanoscale clusters at ER-PM junctions upon store depletion; STIM1 extended molecules bridge a ~12-nm ER-PM gap; Orai1 cluster into puncta on raised membrane subdomains; the stoichiometry of Orai1 channels is unchanged by store depletion or STIM1 co-expression; a portion of Orai1 channels are spaced ~15 nm apart, consistent with interaction with small STIM1 clusters.\",\n      \"method\": \"Transmission and freeze-fracture electron microscopy of STIM1/Orai1-expressing HEK293 cells, thapsigargin-induced store depletion, Monte Carlo analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct ultrastructural visualization by two EM methods with quantitative analysis, single rigorous study\",\n      \"pmids\": [\"26351694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ER Ca2+ store depletion induces STIM1 phosphorylation at tyrosine 361 (Y361) via Pyk2 kinase; the phospho-defective Y361F mutant forms puncta but fails to recruit Orai1, preventing SOCE; in mouse lungs, Y361F expression prevented PAR1-induced vascular permeability increase.\",\n      \"method\": \"Site-directed mutagenesis (Y361F), phospho-specific detection, co-localization imaging, Pyk2 kinase identification, SOCE measurements, in vivo vascular permeability assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase identification with mutagenesis and in vivo functional validation, single lab\",\n      \"pmids\": [\"28218251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIM1 is transported by microtubule plus ends to the front of migrating endothelial leader cells; local ER Ca2+ depletion at the front activates STIM1; polarized STIM1 activity supports pulsatile front retraction and adhesion during directed cell migration.\",\n      \"method\": \"Live-cell fluorescence imaging of STIM1 and microtubule dynamics, STIM1 localization in migrating leader cells, Ca2+ imaging\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell localization tied to functional migration phenotype, single lab\",\n      \"pmids\": [\"24463606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STIM1 concentration controls the magnitude of store-operated Ca2+ entry, and elevated STIM1 concentration activates a Ca2+-driven, PKC-δ- and RasGRP-dependent proapoptotic Erk signaling pathway in developing B cells; overexpression of STIM1 conferred a competitive disadvantage to developing B cells; this pathway is biochemically distinct from DAG-induced Erk activation.\",\n      \"method\": \"Genetic mouse models (PKC-δ KO, STIM1 overexpression), biochemical pathway analysis, epistasis with PKC-δ and RasGRP\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in multiple mouse models with biochemical pathway dissection, single lab\",\n      \"pmids\": [\"21441934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 at a site adjacent to the STIM1-Orai1 coupling region; this interaction disrupts the STIM1-Orai1 complex and disassembles STIM1 oligomers, facilitating slow Ca2+-dependent inactivation of SOCE.\",\n      \"method\": \"Co-immunoprecipitation, CaM-binding site mapping by mutagenesis, SOCE/ICRAC measurements with wild-type and constitutively active STIM1 mutant, STIM1 oligomer analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding site identification by mutagenesis with functional SOCE/inactivation readout and oligomer disruption assay in a single rigorous study\",\n      \"pmids\": [\"29051492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STIM1 helix α3 (residues 400-403) within SOAR/CAD does not mediate initial STIM1-Orai1 interaction but is essential for transmitting STIM1 binding into Orai1 channel gating; cysteine crosslinking revealed proximity of STIM1 α3 to Orai1 TM3, defining a STIM1-Orai1 gating interface (SOGI).\",\n      \"method\": \"Mutagenesis of STIM1 α3, cysteine crosslinking, co-immunoprecipitation, electrophysiology\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crosslinking defines physical interface, mutagenesis dissects binding vs. gating, functional electrophysiology validation in one study\",\n      \"pmids\": [\"30831274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STIM1 contains a cholesterol-binding domain located within the SOAR region; STIM1/SOAR associates functionally with cholesterol at the inner plasma membrane leaflet; cholesterol depletion causes SOAR detachment from the plasma membrane and enhances SOAR-Orai1 association.\",\n      \"method\": \"Protein-lipid interaction assays, fluorescence microscopy, cholesterol depletion, SOAR domain constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-lipid binding assay with functional consequence shown, single lab, two orthogonal methods\",\n      \"pmids\": [\"27459950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STIM1 SOAR oligomerization promotes direct interaction with plasma membrane phosphoinositides to trap STIM1 at ER-PM contact sites; a cluster of conserved lysine residues within SOAR mediates this lipid interaction; the interaction is co-regulated by STIM1 coiled-coil 1 and inactivation domains.\",\n      \"method\": \"Electron and fluorescence microscopy, protein-lipid interaction assays, mutagenesis of SOAR lysine cluster\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein-lipid binding with structural imaging and mutagenesis, single lab\",\n      \"pmids\": [\"36906853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Calsequestrin 1 (CSQ1) physically interacts with STIM1; increased monomeric CSQ1 enhances CSQ1-STIM1 interaction and reduces STIM1-Orai1 association and SOCE; C-terminal deletions in CSQ1 abolish its ability to modulate STIM1-Orai1 interaction.\",\n      \"method\": \"Co-immunoprecipitation, CSQ1 overexpression and deletion mutants, SOCE measurements in HEK293 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with deletion mutant dissection and functional SOCE readout, single lab\",\n      \"pmids\": [\"26087026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Surf4 associates with STIM1 in the ER (identified by affinity purification); deletion of Surf4 in DT40 B cells markedly increases SOCE and facilitates STIM1 clustering upon store depletion, indicating Surf4 is a negative modulator of STIM1-mediated SOCE.\",\n      \"method\": \"Affinity purification/mass spectrometry for binding partner identification, Surf4 knockout DT40 cells, SOCE measurements, STIM1 clustering assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner identified by affinity purification with functional KO validation, single lab\",\n      \"pmids\": [\"22609200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Desmin (major skeletal muscle intermediate filament protein) interacts with the CC1-SOAR domains of STIM1; desmin-STIM1 interaction enhances STIM1 oligomerization yet limits SOCE; in desmin-KO mice, STIM1 retention at the Z-line is lost and SR Ca2+ refilling efficiency is altered.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunolocalization, desmin-KO mouse analysis, Ca2+ signaling measurements\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner identified by Y2H validated by co-IP and KO mouse with functional readout, single lab\",\n      \"pmids\": [\"34494555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STIM1 constitutively maintains ER-PM peripheral coupling in contractile vascular smooth muscle cells (VSMCs) independent of ER Ca2+ store depletion; STIM1 KO in VSMCs reduces the number/size of SR-PM junctions, disrupts nanoscale colocalization of Ca2+-release sites with Ca2+-activated channels, diminishes channel activity, and causes hypotension and blunted arterial contractility.\",\n      \"method\": \"SMC-specific inducible STIM1 knockout mice, SR-PM junction imaging, nanoscale colocalization analysis, Ca2+ signaling, vascular contractility measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal structural and functional readouts, in vivo physiological phenotype\",\n      \"pmids\": [\"35147077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A neuronal splice variant STIM1B, containing an inserted domain B, shows exclusive neuronal expression, slower ER-PM cluster formation kinetics, slower ICRAC activation, and reduced inactivation compared to canonical STIM1; STIM1B targets to presynaptic sites via domain B and converts synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement at high-frequency stimulation.\",\n      \"method\": \"Cloning and characterization of STIM1B splice variant, ICRAC electrophysiology, live imaging of cluster formation, presynaptic targeting, synaptic plasticity recordings in primary neurons\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — novel isoform functionally characterized by electrophysiology, imaging, and synaptic physiology in primary neurons in a single rigorous study\",\n      \"pmids\": [\"33730587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STIM1 deficiency in macrophages abolishes FcγR-induced Ca2+ entry and phagocytosis; STIM1-deficient mice are resistant to experimental immune thrombocytopenia, anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis, establishing STIM1 as an essential component of FcγR activation.\",\n      \"method\": \"STIM1 conditional knockout macrophages, Ca2+ imaging, phagocytosis assay, multiple in vivo disease models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple in vitro and in vivo functional readouts across several disease models\",\n      \"pmids\": [\"18941110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STIM1 in the plasma membrane (constitutively surface-localized pool) regulates ARC (arachidonic acid-regulated Ca2+-selective) channels in a manner independent of store depletion, EF-hand Ca2+ binding, and STIM1 translocation to the plasma membrane; extracellular antibody targeting the N-terminal domain of STIM1 selectively inhibits ARC channel activity; mutations preventing N-glycosylation-dependent plasma membrane expression of STIM1 specifically inhibit ARC channels without affecting CRAC.\",\n      \"method\": \"Extracellular antibody inhibition, N-glycosylation mutants preventing PM expression, CRAC vs. ARC channel current recordings\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct antibody-block and glycosylation mutant approaches with separate channel current readouts, single lab\",\n      \"pmids\": [\"17391754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STIM1 regulates TRPC6 expression at the plasma membrane, causing translocation of TRPC6 to the ER; STIM1-mediated TRPC6 internalization reduces TRPC6-TRPC1 and TRPC6-TRPC3 heteromultimerization; TRPC6 expression in the ER increases passive Ca2+ efflux and basal cytosolic Ca2+.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, TRPC6 localization imaging, Ca2+ measurements\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and localization with functional Ca2+ readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"25088676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by facilitating invadopodium precursor assembly via Src activation; Orai1 blockade inhibits MT1-MMP recycling to the plasma membrane and entraps MT1-MMP in endocytic compartments, inhibiting ECM degradation; STIM1 knockdown significantly inhibited melanoma lung metastasis in a xenograft model.\",\n      \"method\": \"Ca2+ imaging, STIM1/Orai1 knockdown, invadopodium assembly assays, MT1-MMP trafficking assays, xenograft mouse model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway placement with trafficking assay and in vivo xenograft, single lab\",\n      \"pmids\": [\"25404747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ER-resident STIM1/2 physically interacts with pannexin-1 (Panx1) at a hydrophobic region within the Panx1 N-terminus; STIM recruitment couples Ca2+ entry via NMDARs to large-pore Panx1 activation; a Panx1 N-terminus-recognizing antibody blocks large-pore activation by STIM1/2.\",\n      \"method\": \"Co-immunoprecipitation, interaction interface mapping with Panx1 deletion mutants, function-blocking antibody, Ca2+ entry assays in neurons\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding interface mapped by deletion mutagenesis with functional antibody-block and KO neuron validation, single lab\",\n      \"pmids\": [\"36037373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STIM1 phosphorylation at Y316 positively regulates STIM1-Orai1 colocalization and SOCE/ICRAC; the phospho-defective Y316F mutant reduces STIM1 tyrosine phosphorylation, SOCE, and ICRAC; Y316F alters STIM1-SARAF interaction under both resting and Ca2+-store-depleted conditions and enhances slow Ca2+-dependent inactivation.\",\n      \"method\": \"Y316F mutagenesis, STIM1-Orai1 colocalization imaging, SOCE and ICRAC measurements, STIM1-SARAF co-immunoprecipitation, SARAF knockdown epistasis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts and epistasis with SARAF, single lab\",\n      \"pmids\": [\"30975919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STIM1 promotes cell migration in vascular smooth muscle cells (VSMCs); STIM1 interacts with TRPC1 in VSMCs; extracellular antibody against the N-terminal STIM1 domain inhibits store-depletion-evoked Ca2+ current and cell migration but not proliferation; plasma-membrane-localized STIM1 contributes to TRPC1-independent store-operated cationic current and migration.\",\n      \"method\": \"STIM1 siRNA, extracellular antibody application, Ca2+ entry and current measurements, migration assays, co-immunoprecipitation\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct antibody-block of surface STIM1 with migration and current readouts, co-IP for binding, single lab\",\n      \"pmids\": [\"18802022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TSPAN18 directly interacts with STIM1 and competitively inhibits TRIM32-mediated ubiquitination and degradation of STIM1, thereby increasing STIM1 protein stability and SOCE-dependent Ca2+ influx.\",\n      \"method\": \"LC-MS/MS identification of TSPAN18, co-immunoprecipitation, TRIM32 ubiquitination assay, STIM1 stability measurements\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding and competitive ubiquitination mechanism identified by co-IP and functional assay, single lab\",\n      \"pmids\": [\"37542345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ERK1/2-mediated phosphorylation of STIM1 at Ser575, Ser608, and Ser621 is triggered by EGF/H-Ras signaling and promotes STIM1 dissociation from EB1 (microtubule plus-end regulator); phospho-defective Ser-to-Ala mutations impair EGF-triggered cell migration while phosphomimetic mutations restore it; STIM1 phosphorylation is upstream of Ca2+ entry activation.\",\n      \"method\": \"Site-directed mutagenesis (S575A/S608A/S621A and S575E/S608E/S621E), ERK1/2 inhibition, STIM1-EB1 co-immunoprecipitation, migration assays, EMT marker analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site mutagenesis with functional migration readout and upstream kinase identification, single lab\",\n      \"pmids\": [\"25447552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STIM1 ablation in dendritic cells impairs antigen cross-presentation and chemotaxis in vivo and in vitro; STIM1 deficiency disrupts phagosomal proteolysis, leucyl aminopeptidase activity, IRAP recruitment, and phagosome-endolysosome fusion without affecting phagosomal pH or ROS production; STIM1-dependent Ca2+ signaling promotes delivery of endolysosomal enzymes to phagosomes.\",\n      \"method\": \"Stim1 conditional KO in myeloid cells, cross-presentation assay, chemotaxis assay, phagosomal pH and ROS measurements, phagosome-endolysosome fusion assay, IRAP localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple mechanistic readouts in vivo and in vitro identifying a specific phagosomal trafficking function\",\n      \"pmids\": [\"29176619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STIM1 stabilizes Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway during HCC tumor growth; downregulated STIM1 in metastatic HCC cells shifts metabolism from glycolysis toward AMPK-activated fatty acid oxidation (FAO), promoting anoikis-resistance and metastasis driven by Snail1; Snail1 suppresses STIM1/SOCE during metastasis creating a feedback loop.\",\n      \"method\": \"CRISPR-Cas9 STIM1 KO, lentiviral overexpression, Seahorse metabolic analysis, in vivo lung metastasis model, pathway (CaMKII/AKT/GSK-3β) analysis\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with metabolic and signaling pathway mechanistic readouts and in vivo validation, single lab\",\n      \"pmids\": [\"32483465\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STIM1 is an ER-resident single-pass transmembrane Ca2+ sensor that, upon ER Ca2+ depletion, undergoes conformational changes (initiated by Ca2+ dissociation from its luminal EF-hand and other luminal Ca2+-binding sites, causing SAM-domain hydrophobic-cleft disassembly) leading to STIM1 oligomerization and translocation to ER-PM junctions, where its SOAR/CAD domain (residues 344-442) directly gates Orai1 channels via a unimolecular coupling mechanism and its polybasic domain (K684/K685) electrostatically gates TRPC1/4 channels; STIM1 activity is modulated by S-glutathionylation at C56 (oxidant activation), phosphorylation at Y361 by Pyk2 (required for Orai1 recruitment), phosphorylation at ERK1/2-target serines (promotes migration), phosphorylation at Y316 (regulates SARAF interaction and inactivation), and TRIM32-mediated ubiquitination (degradation opposed by TSPAN18); Ca2+-bound calmodulin binds activated STIM1 to disrupt STIM1-Orai1 complexes and STIM1 oligomers for slow inactivation; a plasma-membrane pool of STIM1 constitutively regulates ARC channels and platelet function; in contractile VSMCs STIM1 constitutively maintains SR-PM peripheral coupling independent of store depletion; a neuronal splice variant STIM1B targets to presynaptic sites to confer short-term synaptic enhancement; and STIM1-dependent SOCE controls diverse physiological processes including T-cell activation at the immunological synapse, dendritic-cell cross-presentation, FcγR-mediated phagocytosis, B-cell negative selection, invadopodium-driven cancer invasion, and enamel mineralization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STIM1 is an ER-resident single-pass transmembrane Ca2+ sensor that couples depletion of ER Ca2+ stores to activation of plasma-membrane Ca2+ channels, driving store-operated Ca2+ entry (SOCE) across diverse physiological settings [#1, #11]. Sensing operates through the luminal domain, which carries the canonical EF-hand plus several additional energetically coupled Ca2+-binding sites; Ca2+ dissociation destabilizes the EF-hands and triggers disassembly of a hydrophobic cleft formed with the SAM domain, switching the protein into an activated conformation rather than unfolding it [#11, #12]. Disease- and cancer-associated mutations in the EF-hand or hydrophobic cleft, and a gain-of-function mutation in coiled-coil 1 (R304W) that causes a platelet bleeding disorder, lock STIM1 into a constitutively clustered, channel-activating state [#9, #12]. Activated STIM1 oligomerizes and is trapped at ER-PM junctions through SOAR-domain interactions with plasma-membrane phosphoinositides and cholesterol, bridging a ~12-nm ER-PM gap to form nanoscale clusters with its target channels [#13, #19, #20]. The SOAR/CAD region (residues 344-442) is necessary and sufficient to gate Orai channels, with helix \\u03b13 transmitting binding into channel opening at a defined STIM1-Orai1 gating interface, operating through a unimolecular coupling mechanism [#0, #10, #18]. Beyond Orai, the polybasic lysine-rich domain electrostatically gates TRPC1/4 channels [#1, #6]. STIM1 activity is tuned by phosphorylation (Pyk2 at Y361 for Orai1 recruitment, Y316 regulating SARAF interaction and inactivation, ERK1/2 serines promoting migration), by S-glutathionylation at C56 conferring oxidant-activated Ca2+ entry, by Ca2+-calmodulin-mediated complex disassembly driving slow inactivation, and by TRIM32-mediated ubiquitination opposed by TSPAN18 [#2, #14, #17, #31, #33, #34]. Through these mechanisms STIM1-dependent Ca2+ signaling controls T-cell and Fc\\u03b3R immune responses, dendritic-cell cross-presentation, directed cell migration and cancer invasion, vascular smooth-muscle coupling, and, via the neuronal splice variant STIM1B, presynaptic short-term synaptic enhancement [#3, #15, #24, #25, #26, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Before its Ca2+-sensing role was known, STIM1 was characterized biochemically as a phosphorylated, N-glycosylated, cell-surface-localized protein, establishing the basic protein chemistry and a surface pool later revisited functionally.\",\n      \"evidence\": \"Immunofluorescence, surface biotinylation, and PTM analysis in K562 cells\",\n      \"pmids\": [\"11004585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No link to Ca2+ signaling established at this stage\", \"Relative size of surface vs ER pool not quantified\", \"Function of glycosylation/phosphorylation not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that the cytosolic STIM1 C-terminus is sufficient to activate SOC, ICRAC, and TRPC1 channels, and mapped distinct domains (ERM for TRPC binding, lysine-rich region for TRPC1 gating), defining STIM1 as a multi-channel activator.\",\n      \"evidence\": \"Domain deletion constructs, siRNA, electrophysiology, co-IP, dominant-negative analysis\",\n      \"pmids\": [\"16906149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the Orai-activating subregion within the C-terminus\", \"Mechanism of luminal Ca2+ sensing not addressed\", \"Direct vs indirect TRPC gating not distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated a store-independent function for the plasma-membrane STIM1 pool in gating ARC channels, distinguishing it from the ER store-operated mechanism.\",\n      \"evidence\": \"Extracellular antibody block, N-glycosylation mutants, CRAC vs ARC current recordings\",\n      \"pmids\": [\"17391754\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular interface with ARC channels not mapped\", \"Physiological contexts for surface STIM1 not defined here\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the physical coupling logic of activation: store depletion drives direct STIM1-Orai1 interaction with an Orai1 conformational change, STIM1 puncta form at predetermined ER-PM loci, and electrostatic charge-swap experiments defined the polybasic-domain mechanism gating TRPC1.\",\n      \"evidence\": \"Live-cell FRET, EYFP-STIM1 imaging, charge-swap mutagenesis, SOCE pharmacology\",\n      \"pmids\": [\"18832420\", \"18285445\", \"17517433\", \"19574740\", \"18635545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of the STIM1-Orai1 interface unresolved\", \"Identity of factors defining puncta loci unknown\", \"Stoichiometry of coupling not yet determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed STIM1 in immune effector physiology, showing recruitment to the immunological synapse and an essential role in Fc\\u03b3R-mediated Ca2+ entry, phagocytosis, and multiple antibody-driven disease models.\",\n      \"evidence\": \"Live imaging of T-cell/DC conjugates, conditional KO macrophages, in vivo disease models\",\n      \"pmids\": [\"18250319\", \"18941110\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream Ca2+-dependent effectors not fully dissected\", \"Cell-type-specific channel partners not defined\", \"Initial synapse accumulation mechanism (Orai-independent) unexplained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the minimal Orai-activating module SOAR (344-442) as necessary and sufficient to gate all Orai isoforms and showed co-clustering alone is insufficient, separating recruitment from gating.\",\n      \"evidence\": \"Truncation/point mutagenesis, electrophysiology, co-clustering assays in HEK293\",\n      \"pmids\": [\"19182790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residues transmitting binding into gating not yet pinpointed\", \"Conformational basis of SOAR activation unresolved\", \"Structural model of the coupled complex absent\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that STIM1 abundance is a tunable signaling variable, where elevated STIM1 engages a proapoptotic PKC-\\u03b4/RasGRP/Erk pathway in B-cell negative selection distinct from DAG-driven Erk.\",\n      \"evidence\": \"Genetic mouse models and biochemical epistasis\",\n      \"pmids\": [\"21441934\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between SOCE magnitude and Erk activation not biochemically reconstituted\", \"Generalizability beyond developing B cells unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected STIM1 to directed migration and metastasis: microtubule plus-end transport polarizes STIM1 to the migrating front, ERK1/2 phosphorylation at S575/S608/S621 controls EB1 dissociation and migration, and STIM1/Orai1 Ca2+ oscillations drive invadopodium-mediated invasion.\",\n      \"evidence\": \"Live imaging, phospho-site mutagenesis, invadopodium/MT1-MMP trafficking assays, xenograft models\",\n      \"pmids\": [\"24463606\", \"25447552\", \"25404747\", \"18802022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy between trafficking, phosphorylation, and Ca2+ entry not fully ordered\", \"Direct kinase-substrate verification limited\", \"In vivo relevance of EB1 dissociation not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified STIM1 R304W in coiled-coil 1 as a human gain-of-function mutation causing constitutive CRAC activation and a platelet bleeding/preactivation phenotype, demonstrating CC1 maintains the resting state.\",\n      \"evidence\": \"Patient genetics, heterologous expression, platelet Ca2+ measurements, zebrafish model\",\n      \"pmids\": [\"24591628\", \"24619930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism by which CC1 enforces autoinhibition not resolved\", \"Full spectrum of clinical manifestations not delineated\", \"Relationship to tubular aggregate myopathy mutations not addressed here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided structural and mechanistic refinement of activation: ultrastructural imaging showed STIM1 bridges a ~12-nm ER-PM gap forming nanoscale Orai1 clusters, and concatemer-dimer mutagenesis established a unimolecular STIM1-Orai1 coupling mechanism.\",\n      \"evidence\": \"EM and freeze-fracture imaging, SOAR F394H concatemer dimers, electrophysiology\",\n      \"pmids\": [\"26351694\", \"26399906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact stoichiometry of STIM1 per Orai1 hexamer not fixed\", \"Dynamics of cluster assembly not captured\", \"Lipid contribution to junction formation not yet defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified luminal/ER modulators CSQ1 and Surf4 as negative regulators that limit STIM1-Orai1 association and clustering, adding upstream brakes on SOCE.\",\n      \"evidence\": \"Co-IP, deletion mutants, KO cells, SOCE measurements\",\n      \"pmids\": [\"26087026\", \"22609200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological settings where these brakes dominate unclear\", \"Direct vs indirect modulation not fully separated\", \"Single-lab findings\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SOAR contains a cholesterol-binding domain and that membrane lipid composition governs SOAR-PM attachment and SOAR-Orai1 association, introducing lipid regulation of coupling.\",\n      \"evidence\": \"Protein-lipid assays, cholesterol depletion, SOAR constructs\",\n      \"pmids\": [\"27459950\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of cholesterol regulation untested\", \"Interplay with phosphoinositide binding not resolved here\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined regulatory inputs controlling activation and inactivation: Pyk2 phosphorylation at Y361 is required for Orai1 recruitment, and Ca2+-calmodulin binding adjacent to the coupling region disassembles STIM1-Orai1 complexes and oligomers for slow inactivation.\",\n      \"evidence\": \"Mutagenesis, phospho-detection, CaM-binding mapping, SOCE/inactivation assays, in vivo vascular permeability\",\n      \"pmids\": [\"28218251\", \"29051492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal coordination of Y361 phosphorylation with clustering unclear\", \"CaM-binding site structure not solved\", \"Crosstalk between these regulatory layers unmapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a specific intracellular trafficking function of STIM1 in dendritic cells, showing Ca2+ signaling promotes endolysosomal enzyme delivery and phagosome-endolysosome fusion required for cross-presentation, independent of phagosomal pH and ROS.\",\n      \"evidence\": \"Myeloid conditional KO, cross-presentation, chemotaxis, phagosome fusion and IRAP assays\",\n      \"pmids\": [\"29176619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Ca2+ targets controlling fusion not identified\", \"Channel partner in dendritic cells not specified here\", \"Link between chemotaxis and trafficking defects not separated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the luminal sensing mechanism in molecular detail, demonstrating 5-6 Ca2+-binding sites energetically coupled to the canonical EF-hand and that Ca2+ loss drives a conformational switch rather than unfolding.\",\n      \"evidence\": \"Biophysical Ca2+-binding, structural analysis, mutagenesis, cell SOCE assays\",\n      \"pmids\": [\"30382093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic structure of the activated luminal state incomplete\", \"How luminal switch propagates to cytosolic SOAR not resolved here\", \"Quantitative Ca2+ thresholds in cells not fixed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined activation mechanics: MD plus live-cell work resolved sequential luminal conformational changes, helix \\u03b13 (400-403) was shown to transmit binding into Orai1 gating at a defined gating interface (SOGI), and Y316 phosphorylation was tied to SARAF interaction and inactivation.\",\n      \"evidence\": \"MD simulations, cysteine crosslinking, mutagenesis, electrophysiology, co-IP\",\n      \"pmids\": [\"31744929\", \"30831274\", \"30975919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the gated STIM1-Orai1 interface still absent\", \"Kinase responsible for Y316 not identified here\", \"Integration of \\u03b13 gating with luminal switch not mechanistically continuous\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded the partner and tissue repertoire: desmin retains STIM1 at the skeletal-muscle Z-line and modulates SOCE, and a neuronal splice variant STIM1B targets presynaptic sites to convert synaptic depression into Ca2+/Orai-dependent short-term enhancement.\",\n      \"evidence\": \"Y2H, co-IP, KO mouse, splice-variant cloning, ICRAC and synaptic plasticity recordings\",\n      \"pmids\": [\"34494555\", \"33730587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which STIM1B insertion alters kinetics not structurally defined\", \"Desmin-STIM1 interface not mapped at residue level\", \"Generality of STIM1B function across synapse types unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated a store-depletion-independent constitutive role for STIM1 in maintaining ER-PM peripheral coupling in contractile vascular smooth muscle and a novel ER-STIM/pannexin-1 coupling mechanism in neurons.\",\n      \"evidence\": \"SMC-specific inducible KO with junction imaging and contractility; Panx1 interface mapping with function-blocking antibody\",\n      \"pmids\": [\"35147077\", \"36037373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinants of constitutive coupling vs store-operated mode not separated\", \"Panx1-STIM physiological output beyond Ca2+ entry unclear\", \"Conservation across smooth-muscle beds untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified protein-stability and lipid-trapping control of STIM1: SOAR oligomerization engages PM phosphoinositides to trap STIM1 at ER-PM contacts, and TSPAN18 competitively blocks TRIM32-mediated ubiquitination to stabilize STIM1 and boost SOCE.\",\n      \"evidence\": \"EM/fluorescence imaging, protein-lipid assays, LC-MS/MS, co-IP, ubiquitination and stability assays\",\n      \"pmids\": [\"36906853\", \"37542345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Triggers controlling TRIM32 vs TSPAN18 balance in vivo unclear\", \"Coordination of phosphoinositide and cholesterol binding unresolved\", \"Single-lab mechanistic claims\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the discrete regulatory layers (luminal Ca2+ switch, phosphorylation, glutathionylation, CaM/SARAF inactivation, lipid trapping, and ubiquitin-mediated turnover) are integrated in time and space to produce graded, tissue-specific SOCE remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the activated full-length STIM1-Orai1 complex\", \"Quantitative model linking regulatory inputs to channel output absent\", \"Mechanistic basis for switching between store-operated and constitutive coupling modes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 6, 18, 27]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [19, 20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 13, 24]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 27, 32]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [13, 20, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 26, 35]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 11, 13]}\n    ],\n    \"complexes\": [\"STIM1-Orai1 CRAC channel complex\"],\n    \"partners\": [\"ORAI1\", \"TRPC1\", \"CALM1\", \"SARAF\", \"TSPAN18\", \"TRIM32\", \"DES\", \"PANX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":8,"faith_total":8,"faith_pct":100.0}}