Affinage

STIM1

Stromal interaction molecule 1 · UniProt Q13586

Length
685 aa
Mass
77.4 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STIM1 is an ER-resident single-pass transmembrane protein that functions as the primary sensor of ER luminal Ca²⁺ depletion, coupling store emptying to activation of plasma membrane Ca²⁺ channels and additional non-canonical signaling pathways. Its luminal EF-hand/SAM domain binds Ca²⁺ at multiple cooperatively coupled sites; upon Ca²⁺ dissociation, sequential conformational changes—destabilization of the EF-hand hydrophobic cleft, reorganization of the transmembrane domain, and release of the CC1–CC3 intramolecular clamp—expose the SOAR/CAD domain, which oligomerizes, translocates to ER–PM junctions via phosphoinositide interactions, and directly gates Orai1 CRAC channels through a STIM1 α3–Orai1 TM3 gating interface, while also activating TRPC1 channels via electrostatic interactions of its polybasic tail (PMID:15866891, PMID:19182790, PMID:30831274, PMID:19574740, PMID:33106661, PMID:36906853). Beyond canonical store-operated Ca²⁺ entry, STIM1 independently activates RhoA-mediated endothelial barrier regulation, couples NMDAR Ca²⁺ entry to Pannexin-1 large-pore opening in neurons, interacts with Rictor to regulate mTORC2/Akt signaling in cardiomyocytes, and promotes phagosomal maturation in dendritic cells; its activity is modulated by S-glutathionylation at C56, phosphorylation at Y361/Y316 and ERK1/2 sites, calmodulin-mediated STIM1–Orai1 complex disassembly, TRIM32-mediated ubiquitination, and interactions with calsequestrin, Surf4, desmin, and cholesterol (PMID:23512989, PMID:36037373, PMID:26936863, PMID:29176619, PMID:20679432, PMID:28218251, PMID:29051492, PMID:37542345, PMID:34494555). Gain-of-function mutations in the CC1 domain (e.g., R304W) cause constitutive CRAC channel activation and Stormorken syndrome (PMID:24591628, PMID:33106661).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 Medium

    Before STIM1's function was known, early characterization established it as a glycosylated, serine-phosphorylated transmembrane protein present both at the cell surface and in intracellular compartments, setting the stage for its later identification as an ER Ca²⁺ sensor.

    Evidence Immunofluorescence, surface biotinylation, and phosphorylation analysis in K562 cells

    PMID:11004585

    Open questions at the time
    • Function and physiological role entirely unknown at this point
    • ER versus PM localization unclear in terms of functional relevance
  2. 2005 High

    A genome-wide RNAi screen identified STIM1 as an essential, conserved component of store-operated/CRAC channel function, establishing it as the long-sought link between ER Ca²⁺ store depletion and PM Ca²⁺ entry.

    Evidence RNAi knockdown in Drosophila S2, Jurkat, HEK293, and SH-SY5Y cells with patch-clamp and Ca²⁺ imaging

    PMID:15866891

    Open questions at the time
    • Mechanism by which STIM1 senses store depletion unknown
    • Whether STIM1 directly contacts PM channels unknown
  3. 2006 High

    Demonstrating that the STIM1 cytosolic tail suffices to activate SOC, CRAC, and TRPC1 channels resolved whether STIM1 acts as a direct channel activator or an upstream signal relay, and identified selectivity among TRPC family members.

    Evidence Dominant-negative mutant expression, siRNA, Co-IP, patch-clamp in HEK293 and Jurkat cells

    PMID:16906149

    Open questions at the time
    • Minimal activating domain within the cytosolic tail not yet defined
    • Direct versus indirect TRPC gating mechanism unclear
  4. 2008 High

    Live-cell FRET demonstrated that store depletion triggers physical STIM1–Orai1 interaction and Orai1 conformational rearrangement at ER–PM junctions, establishing a direct coupling model for CRAC channel activation.

    Evidence Live-cell FRET microscopy and patch-clamp with mutagenesis in HEK293 cells; STIM1 puncta dynamics with pharmacological agents

    PMID:18285445 PMID:18832420

    Open questions at the time
    • Stoichiometry of the STIM1–Orai1 complex undefined
    • Molecular determinants of the gating interface not mapped
  5. 2009 High

    Identification of the SOAR domain (aa 344–442) as the minimal Orai-activating fragment, and mapping of the polybasic domain's electrostatic gating of TRPC channels, defined the modular architecture of STIM1's effector functions; the role of PM phosphoinositides in Orai1 activation was distinguished from STIM1 translocation.

    Evidence Systematic domain deletion/mutagenesis, charge-swap mutagenesis, patch-clamp, Ca²⁺ imaging, PI4K inhibition in HEK293 cells

    PMID:19182790 PMID:19483082 PMID:19574740

    Open questions at the time
    • Autoinhibitory mechanism keeping SOAR inactive in resting STIM1 unknown
    • Independence of TRPC channels from STIM1 debated across studies (PMID:19332491)
  6. 2010 High

    Discovery of the CC1 acidic-motif/CAD intramolecular clamp and S-glutathionylation at C56 revealed two distinct activation switches: one governed by luminal Ca²⁺ sensing (releasing the clamp) and another by oxidant stress (bypassing store depletion).

    Evidence Site-directed mutagenesis of acidic clamp residues and C56, FRET, Co-IP, Ca²⁺ imaging in HEK293 cells

    PMID:20679432 PMID:21081754

    Open questions at the time
    • Structural basis of the CC1–SOAR clamp not determined
    • In vivo significance of S-glutathionylation activation pathway unclear
  7. 2011 High

    STIM1-dependent SOCE was shown to set a threshold for Ca²⁺-driven proapoptotic ERK activation in B cell negative selection, and STIM1 was found in acidic stores of platelets, extending its functional context beyond T cell immunity.

    Evidence STIM1 overexpression/knockdown in B cells with PKC-δ KO mice; organelle fractionation and Co-IP in human platelets

    PMID:21321120 PMID:21441934

    Open questions at the time
    • Whether STIM1 in acidic stores directly senses luminal Ca²⁺ unclear
    • Quantitative relationship between STIM1 levels and signaling threshold not defined
  8. 2013 High

    Conditional STIM1 knockout in myeloid cells established its essential role in FcγR-mediated phagocytosis and autoimmune pathology, while endothelial studies revealed a Ca²⁺/Orai1-independent STIM1 function—coupling thrombin receptors to RhoA activation and barrier disruption.

    Evidence Conditional KO mice with in vivo disease models; siRNA knockdown with RhoA activity and transendothelial resistance assays in endothelial cells

    PMID:18941110 PMID:23512989

    Open questions at the time
    • Molecular mechanism by which STIM1 activates RhoA independently of Ca²⁺ not elucidated
    • Whether non-canonical STIM1 functions involve distinct protein conformations unknown
  9. 2014 High

    Multiple advances converged: the CC1–CC3 coiled-coil clamp mechanism was mapped by FRET, the R304W gain-of-function mutation was linked to Stormorken syndrome, STIM1-driven Ca²⁺ oscillations were shown to orchestrate melanoma invadopodium assembly, and STIM1 was found to be transported to the cell front via microtubule plus-ends during directed migration.

    Evidence FIRE FRET assay with mutagenesis; zebrafish Stormorken model with patch-clamp; invadopodium/xenograft assays; live-cell imaging in migrating endothelial cells; ERK phospho-site mutagenesis

    PMID:24463606 PMID:24591628 PMID:25342749 PMID:25404747 PMID:25447552

    Open questions at the time
    • Atomic structure of the CC1–CC3 clamp not available
    • How ERK-mediated phosphorylation integrates with the clamp mechanism unclear
  10. 2015 High

    Transmembrane domain reorganization (rather than oligomeric state change) was identified as the initial step propagating luminal Ca²⁺ loss to cytoplasmic conformational extension; ultrastructural EM revealed STIM1 bridges a 12-nm ER–PM gap; calsequestrin and Homer1 were identified as modulators of STIM1 oligomerization and L-type channel coupling, respectively.

    Evidence TM gain-of-function mutagenesis with FRET; freeze-fracture EM; Co-IP of CSQ1–STIM1 and Homer1–STIM1–Cav1.2 complexes

    PMID:25712868 PMID:26087026 PMID:26184105 PMID:26351694

    Open questions at the time
    • Atomic resolution structure of full-length STIM1 still lacking
    • Whether CSQ1 regulation is physiologically rate-limiting in non-muscle cells unknown
  11. 2016 High

    STIM1 was found to directly interact with Rictor/mTORC2 in cardiomyocytes and to bind cholesterol via its SOAR domain, revealing non-canonical signaling outputs and lipid-dependent regulatory inputs.

    Evidence Co-IP of STIM1–Rictor with in vivo shRNA and pressure overload models; cholesterol-binding assay, FRET, and Ca²⁺ imaging

    PMID:26936863 PMID:27459950

    Open questions at the time
    • Whether STIM1–Rictor interaction requires Ca²⁺ store depletion not established
    • Cholesterol-binding site residues not precisely mapped
  12. 2017 High

    Pyk2-mediated phosphorylation at Y361 was identified as a gating requirement for Orai1 recruitment into STIM1 puncta, and calmodulin was shown to bind activated STIM1 to disassemble the STIM1–Orai1 complex during slow Ca²⁺-dependent inactivation; STIM1 was also linked to phagosomal maturation and cross-presentation in DCs.

    Evidence Phospho-specific antibody and Y361F mutagenesis with in vivo lung permeability; CaM-binding site mutagenesis with FRET and SOCE; conditional STIM1 KO in DCs with phagosomal assays

    PMID:28218251 PMID:29051492 PMID:29176619

    Open questions at the time
    • Whether Y361 phosphorylation alters the CC1–SOAR clamp conformation unknown
    • Structural basis of CaM-mediated disassembly not resolved
  13. 2018 High

    The luminal EF-hand/SAM domain was shown to possess 5–6 cooperatively coupled Ca²⁺-binding sites (not a single site), and Ca²⁺ dissociation drives a switch to an alternative structured conformation rather than unfolding; preformed STIM1–Orai1–RYR1 nanocomplexes were observed in resting T cells.

    Evidence In vitro Ca²⁺ binding with mutagenesis and functional imaging; super-resolution microscopy and Co-IP/FRET in primary T cells

    PMID:30382093 PMID:30563862

    Open questions at the time
    • High-resolution structure of the multi-Ca²⁺-bound versus Ca²⁺-free luminal domain not available
    • Functional significance of preformed complexes for CRAC activation kinetics not quantified
  14. 2019 High

    Cysteine crosslinking mapped the STIM1 α3–Orai1 TM3 gating interface (SOGI), distinguishing binding from gating; MD simulations of the luminal domain defined the sequential conformational cascade from EF-hand destabilization to hydrophobic cleft disassembly, with disease mutations causing constitutive activation.

    Evidence Cysteine crosslinking and patch-clamp in HEK293; MD simulations with mutagenesis and clustering/Ca²⁺ assays

    PMID:30831274 PMID:31744929

    Open questions at the time
    • Full cryo-EM structure of the STIM1–Orai1 complex at the gating interface not yet obtained
    • Whether the same gating interface is used for TRPC channels unknown
  15. 2020 High

    NMR solution structure of the CC1 three-helix bundle defined the two interhelical sites controlling the CC1–CC3 clamp, directly explaining how Stormorken R304W disrupts autoinhibition; optogenetic STIM1 tools validated the modular oligomerization–conformational switch–target interaction sequence.

    Evidence Solution NMR with mutagenesis and FRET; optogenetic STIM1 module engineering with Ca²⁺ imaging in HEK293 cells

    PMID:32098964 PMID:33106661

    Open questions at the time
    • Full-length STIM1 structure integrating luminal, TM, and cytoplasmic domains still missing
    • How CC1 structural dynamics couple to TM reorganization in real time not captured
  16. 2021 High

    Desmin was identified as a STIM1 binding partner that enhances its oligomerization yet limits SOCE at the sarcomeric Z-line, and a neuronal splice variant STIM1B was shown to slow CRAC kinetics and convert synaptic depression into short-term enhancement at presynaptic terminals.

    Evidence Yeast 2-hybrid, Co-IP, desmin-KO mice; splice variant characterization with ICRAC and synaptic physiology in primary neurons

    PMID:33730587 PMID:34494555

    Open questions at the time
    • Whether desmin regulation of STIM1 is altered in desminopathies not tested
    • STIM1B tissue-specific splicing regulation not characterized
  17. 2022 High

    STIM1 was found to couple NMDAR Ca²⁺ entry to Pannexin-1 large-pore activation in neurons, with the binding interface mapped to a hydrophobic Panx1 N-terminal region, establishing a SOCE-independent neuronal STIM1 signaling axis.

    Evidence Co-IP, domain deletion mutagenesis, function-blocking antibody, Panx1 KO neuron reconstitution

    PMID:36037373

    Open questions at the time
    • Whether STIM1 conformational state influences Panx1 gating efficiency unknown
    • Relevance to excitotoxicity or neurodegeneration not tested in vivo
  18. 2023 High

    The SOAR domain was shown to directly bind PM phosphoinositides via conserved lysine residues for ER–PM tethering (dual function with Orai1 activation), and TRIM32 was identified as an E3 ubiquitin ligase controlling STIM1 stability, competitively inhibited by TSPAN18.

    Evidence Protein-lipid overlay, liposome sedimentation, EM, mutagenesis; Co-IP, ubiquitination assay, CRISPR KO, in vivo metastasis model

    PMID:36906853 PMID:37542345

    Open questions at the time
    • How phosphoinositide binding by SOAR is coordinated with Orai1 gating in time not resolved
    • Whether TRIM32-mediated degradation is tissue-specific unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length atomic structure of STIM1 in resting and activated states, and of the STIM1–Orai1 complex at the gating interface, remains unavailable; how STIM1 integrates its canonical Ca²⁺-sensing function with non-canonical outputs (RhoA, mTORC2, Pannexin-1) through shared or distinct conformational states is mechanistically unresolved.
  • No full-length STIM1 cryo-EM or crystal structure
  • Structural basis for Ca²⁺-independent RhoA activation by STIM1 unknown
  • How post-translational modifications (Y361, Y316, ERK sites, ubiquitination) are integrated into the CC1–SOAR clamp model not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0008289 lipid binding 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-382551 Transport of small molecules 4 R-HSA-168256 Immune System 3
Complex memberships
STIM1-Orai1 CRAC channel complexSTIM1-TRPC1 SOC complexmTORC2 (via Rictor interaction)

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 STIM1 (and its Drosophila ortholog Stim) is an essential and conserved component of store-operated Ca2+ (SOC)/CRAC channel function; RNAi-mediated knockdown of Stim in Drosophila S2 cells suppressed CRAC current, and knockdown of human STIM1 in Jurkat T cells similarly reduced CRAC channel activity and thapsigargin- or agonist-dependent Ca2+ entry. RNAi knockdown, patch-clamp electrophysiology, Ca2+ imaging in Drosophila S2 cells, Jurkat T cells, HEK293, and SH-SY5Y cells The Journal of cell biology High 15866891
2006 The cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, ICRAC, and TRPC1 channels; the ERM domain mediates selective binding of STIM1 to TRPC1, 2, and 4 (but not TRPC3, 6, or 7), and a cationic lysine-rich region is essential for gating of TRPC1. Dominant-negative mutant overexpression, siRNA knockdown, Co-IP, Ca2+ imaging, patch-clamp in HEK293 and Jurkat cells Nature cell biology High 16906149
2009 STIM1 amino acid fragment 344-442 (SOAR, STIM1-Orai activating region) is necessary and sufficient to fully activate all Orai channels; SOAR acts in combination with STIM1 (450-485) to regulate interaction strength with Orai1; the polybasic STIM1 (672-685) mediates characteristic inward rectification of Orai1 by interacting with a Pro-rich region in the Orai1 N-terminus; SOAR mutations prevent Orai1 activation but not co-clustering. Domain deletion/mutagenesis, Ca2+ imaging, patch-clamp electrophysiology, Co-IP in HEK293 cells Nature cell biology High 19182790
2008 Store depletion triggers redistribution of STIM1 and co-clustering with Orai1, accompanied by a pronounced increase in FRET between STIM1 and Orai1, demonstrating physical interaction underlies CRAC channel activation; store depletion also induces STIM1-dependent conformational rearrangements within Orai1 (decrease in Orai1-Orai1 FRET). Live-cell FRET microscopy, patch-clamp, mutagenesis in HEK293 cells The Journal of physiology High 18832420
2010 STIM1 is S-glutathionylated at cysteine 56 in response to oxidant stress, which evokes constitutive Ca2+ entry independent of intracellular Ca2+ stores; STIM1- and Orai1-deficient cells are resistant to oxidant stress-induced Ca2+ entry and cell death. S-glutathionylation assay, site-directed mutagenesis (C56), Ca2+ imaging, siRNA knockdown in multiple cell lines The Journal of cell biology High 20679432
2010 STIM1 contains an intramolecular clamp: an acidic motif within the STIM1 coiled-coil region keeps the CAD/SOAR domain inactive; mutations in this acidic region render STIM1 constitutively active, while mutations in a short basic segment of CAD/SOAR prevent Orai1 activation, supporting a model where CAD/SOAR is released from an intramolecular clamp during STIM1 activation. Site-directed mutagenesis, Ca2+ imaging, FRET, co-immunoprecipitation in HEK293 cells Science signaling High 21081754
2000 STIM1 protein is located at the cell surface (plasma membrane) in addition to intracellular compartments; it is a phosphoprotein (phosphorylated predominantly on serine residues) and is N-linked glycosylated; it is not secreted and does not undergo proteolytic processing. Immunofluorescence, cell surface biotinylation, Western blot, phosphorylation analysis in K562 cells Biochimica et biophysica acta Medium 11004585
2008 Reversal of STIM1 puncta formation (from near-PM junctions back to tubular ER distribution) absolutely requires SOCE-dependent store refilling; ML-9, an MLCK inhibitor, causes rapid store-independent reversal of STIM1 puncta and inhibition of SOCE and ICRAC; STIM1 puncta form at specific predetermined cellular loci. Live-cell EYFP-STIM1 fluorescence imaging, patch-clamp, pharmacological inhibition in HEK293 cells Journal of cell science Medium 18285445
2009 STIM1 gates TRPC channels by electrostatic interaction between STIM1 K684/K685 in the polybasic domain and conserved negative charges (aspartates/glutamates) in TRPC1 (D639/D640) and TRPC3 (D697/D698); charge mutants provide direct evidence for TRPC channels as STIM1-regulated SOCs. Charge-swap mutagenesis, Co-IP, Ca2+ imaging, patch-clamp in HEK293 cells Channels (Austin, Tex.) High 19574740
2009 TRPC channels (TRPC1, 3, 5, 6, 7) function independently of STIM1 and Orai1 in HEK293 cells; STIM1 knockdown did not reduce TRPC5 activity and TRPC7-mediated entry was not dependent on STIM1 or Orai1; STIM1/Orai1 signaling and TRPC signaling occur in distinct plasma membrane domains (STIM1 puncta are distinct from lipid rafts). RNAi knockdown, constitutively active STIM1 mutant expression, Ca2+ imaging, lipid raft disruption in HEK293 and vascular smooth muscle cells The Journal of physiology Medium 19332491
2011 STIM1 controls the magnitude of Ca2+ entry in B cells through SOCE, and its concentration sets a threshold for Ca2+-driven, PKC-δ- and RasGRP-dependent proapoptotic Erk activation that mediates negative selection; this pathway is biochemically distinct from DAG-driven Erk activation. Genetic overexpression/knockdown of STIM1, PKC-δ knockout mice, Ca2+ imaging, Erk activation assays in B cells Nature immunology High 21441934
2013 STIM1 macrophages lacking STIM1 cannot activate FcγR-induced Ca2+ entry and phagocytosis; STIM1 deficiency results in resistance to experimental immune thrombocytopenia, anaphylaxis, autoimmune hemolytic anemia, and acute pneumonitis, establishing STIM1 as an essential component of FcγR activation. Conditional STIM1 knockout mice, Ca2+ imaging, phagocytosis assays, in vivo disease models Blood High 18941110
2013 STIM1 controls endothelial barrier function by coupling the thrombin receptor to RhoA activation, myosin light chain phosphorylation, actin stress fiber formation, and loss of cell-cell adhesion, independently of Ca2+ entry and Orai1. siRNA knockdown, STIM1 overexpression, RhoA activity assay, transendothelial electric resistance measurement, myosin light chain phosphorylation assay in endothelial cells Science signaling High 23512989
2014 STIM1 p.R304W gain-of-function mutation in the coiled-coil 1 domain causes constitutive activation of the CRAC channel in vitro; in zebrafish, this results in spontaneous bleeding and reduced thrombocytes, recapitulating Stormorken syndrome. Heterologous expression, Ca2+ imaging, patch-clamp, zebrafish model of Stormorken syndrome Proceedings of the National Academy of Sciences of the United States of America High 24591628
2014 STIM1 co-clustering with Orai1 is controlled by a coiled-coil clamp: CC1-CC3 interaction regulates SOAR/CAD exposure and higher-order oligomerization; disrupting CC1-CC3 interactions leads to constitutive STIM1 activation and Orai1 channel opening. FRET-derived Interaction in a Restricted Environment (FIRE) assay, mutagenesis, Ca2+ imaging in HEK293 cells The Journal of biological chemistry High 25342749
2014 STIM1 is polarized to the front of migrating endothelial leader cells via microtubule plus-end transport, where local ER Ca2+ depletion activates STIM1 to support pulsatile front retraction and adhesion during directed cell migration; diacylglycerol gradient from polarized PLC signaling further promotes persistent forward migration. Live-cell fluorescence imaging, STIM1 overexpression/knockdown, Ca2+ imaging in migrating endothelial cells Nature cell biology High 24463606
2014 STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly (via Src activation) and extracellular matrix degradation; Orai1 blockade inhibited MT1-MMP recycling to the plasma membrane, trapping it in endocytic compartments. STIM1 knockdown, Ca2+ imaging, invadopodium assays, MT1-MMP trafficking assay, xenograft mouse model The Journal of cell biology High 25404747
2015 STIM1 local rearrangement within its transmembrane domain (rather than change in oligomeric state) prompts conformational changes in the cytosolic juxtamembrane coiled-coil region; critical residues within the cytoplasmic domain mediate autoinhibition; STIM1-TM reorganization switches STIM1-CT into an extended conformation, projecting the ORAI-activating domain to gate ORAI1 channels. Gain-of-function TM domain mutation, FRET, Ca2+ imaging, mutagenesis in HEK293 cells Nature communications High 26184105
2015 STIM1 and Orai1 form nanoclusters at ER-PM junctions; extended STIM1 molecules bridge a 12-nm ER-PM gap and rearrange into small clusters following store depletion; Orai1 channels aggregate into puncta on raised membrane subdomains upon store depletion; stoichiometry of Orai1 is unchanged by store depletion or STIM1 co-expression. Transmission electron microscopy, freeze-fracture electron microscopy of STIM1- and Orai1-transfected HEK293 cells Proceedings of the National Academy of Sciences of the United States of America High 26351694
2016 In cardiomyocytes, STIM1 silencing impairs mTORC2 kinase activity and phosphorylation of Akt at S473, leading to enhanced GSK-3β activity and failure of adaptive hypertrophy; STIM1 directly interacts with Rictor, a specific component of mTOR complex 2, placing STIM1 upstream of mTORC2/Akt/GSK-3β signaling in cardiac hypertrophy. In vivo shRNA gene silencing in mice, Co-IP (STIM1-Rictor interaction), mTORC2 kinase assay, Akt phosphorylation assay, pressure overload models Circulation High 26936863
2017 STIM1 phosphorylation at Y361 by Pyk2 kinase upon ER Ca2+ store depletion is required for Orai1 recruitment into STIM1 puncta and SOCE; phospho-defective STIM1-Y361F formed puncta but failed to recruit Orai1 and prevented thrombin-induced vascular permeability in mouse lungs. Site-directed mutagenesis, phospho-specific antibody, Ca2+ imaging, transendothelial resistance, in vivo mouse lung vascular permeability assay Scientific reports High 28218251
2017 Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 at a site adjacent to the STIM1-Orai1 coupling region, disrupts the STIM1-Orai1 complex, disassembles STIM1 oligomers, and facilitates slow Ca2+-dependent inactivation of the CRAC channel. Co-IP, pulldown, mutagenesis of CaM-binding site, Ca2+ imaging, FRET in HEK293 cells Nature communications High 29051492
2018 The STIM1 ER-luminal domain has 5-6 Ca2+-binding sites (not just the single EF-hand); binding at these sites is energetically coupled to the EF-hand site; Ca2+ dissociation controls a switch to a second structured conformation of the luminal domain rather than protein unfolding; other luminal-domain Ca2+-binding sites interact with the EF-hand to control physiological STIM1 activation in cells. In vitro Ca2+ binding assays, mutagenesis, structural characterization, functional Ca2+ imaging in cells Nature communications High 30382093
2018 In unstimulated T cells, ORAI1, RYR1, and STIM1 form preformed nanoscale complexes (diameter ~300 nm) in the subplasmalemmal space confirmed by super-resolution microscopy and Co-IP/FRET; upon TCR stimulation, NAADP-evoked Ca2+ release through RYR1 in coordination with ORAI1 and STIM1/STIM2 rapidly increases Ca2+ microdomains. Super-resolution microscopy, Co-immunoprecipitation, FRET, Ca2+ microdomain imaging in primary T cells Science signaling High 30563862
2019 The STIM1 α3 helical segment (aa 400-403) within CAD/SOAR does not mediate Orai1 binding but instead conveys STIM1 coupling into Orai1 channel gating; cysteine crosslinking revealed close proximity of STIM1 α3 to the cytosolic extension of Orai1 TM3, forming the STIM1-Orai1 gating interface (SOGI). Mutagenesis, cysteine crosslinking, FRET, patch-clamp in HEK293 cells Cell calcium High 30831274
2019 Sequential Ca2+-dependent conformational changes of the luminal STIM1 domain upon activation were determined: Ca2+ dissociation destabilizes the two EF-hands, triggering disassembly of the hydrophobic cleft formed with the SAM domain; canonical EF-hand and hydrophobic cleft mutations associated with tubular aggregate myopathy or cancer yield constitutively clustered STIM1 with active Ca2+ entry through Orai1. Molecular dynamics simulations, site-directed mutagenesis, live-cell clustering assays, Ca2+ imaging Science signaling High 31744929
2020 Optogenetic incorporation of photoreceptors into STIM1 modular domains revealed molecular determinants for STIM1 protein oligomerization, intramolecular conformational switch, and protein-target interactions; light-inducible STIM1 tools enabled reversible control of Ca2+ channel gating, dynamic protein-microtubule interactions, and ER-PM contact site assembly. Optogenetic engineering, FRET, Ca2+ imaging, live-cell microscopy in HEK293 cells Nature communications High 32098964
2020 The NMR-derived solution structure of the STIM1 CC1 domain is a three-helix bundle; two interhelical sites between CC1α1 and CC1α2 helices control the CC1-CC3 clamp strength that governs the balance between tight (inactive) and extended (active) STIM1 conformations; these interactions are disrupted in the Stormorken disease-related STIM1 R304W mutant. Solution NMR structure determination, mutagenesis, FRET-based conformational assay, Ca2+ imaging Nature chemical biology High 33106661
2021 Desmin, the major type III intermediate filament in muscle, is a binding partner for STIM1 (identified by yeast 2-hybrid and confirmed by Co-IP); desmin interacts with the CC1-SOAR domains of STIM1 to enhance STIM1 oligomerization yet limit SOCE; desmin connects STIM1 at the Z-line to regulate the efficiency of Ca2+ refilling of the SR. Yeast 2-hybrid screen, Co-immunoprecipitation, immunolocalization, SOCE measurements in desmin-KO mice JCI insight High 34494555
2021 A neuronal splice variant of STIM1, STIM1B (spliced-in domain B), shows exclusive neuronal expression and slower kinetics of ER-PM cluster formation and ICRAC with reduced inactivation; STIM1B is targeted to presynaptic sites where it converts synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement at high-frequency stimulation. Splice variant characterization, patch-clamp (ICRAC), live-cell STIM1B cluster kinetics, primary neuron Ca2+ imaging, synaptic physiology Cell reports High 33730587
2022 ER-resident STIM1/2 are binding partners of Pannexin-1 (Panx1), interacting at a hydrophobic region within the Panx1 N-terminus; STIM1/2 recruitment couples Ca2+ entry via NMDARs to Panx1 large-pore activation in neurons. Co-immunoprecipitation, domain deletion mutagenesis, function-blocking antibody, Ca2+ imaging, Panx1 KO neuron reconstitution Proceedings of the National Academy of Sciences of the United States of America High 36037373
2023 The SOAR domain of STIM1 directly interacts with plasma membrane phosphoinositides via a conserved cluster of lysine residues to form ER-PM membrane contact sites; this interaction is co-regulated by STIM1 coiled-coil 1 and inactivation domains; SOAR oligomerization promotes direct PM phosphoinositide interaction to trap STIM1 at ER-PM MCSs. Electron microscopy, fluorescence microscopy, protein-lipid interaction assays (protein-lipid overlay, liposome sedimentation), mutagenesis Cell reports High 36906853
2012 Surf4 associates with STIM1 in the endoplasmic reticulum; deletion of Surf4 in DT40 B cells resulted in markedly increased SOCE and facilitated STIM1 clustering upon store depletion, indicating Surf4 negatively modulates STIM1-mediated SOCE. Affinity purification/Co-IP of STIM1-binding proteins, Surf4 knockout DT40 cells, SOCE measurement, STIM1 clustering assay Biochemical and biophysical research communications Medium 22609200
2014 STIM1 phosphorylation at ERK1/2 target sites (Ser575, Ser608, Ser621) is triggered by EGF/H-Ras signaling; Ser-to-Ala mutations impairing phosphorylation reduce cell migration and EMT marker changes (vimentin, E-cadherin) while phosphomimetic mutations restore them; EGF also triggers STIM1 dissociation from EB1 (microtubule plus-end regulator). Phospho-site mutagenesis (S→A and S→E), pharmacological ERK inhibition, wound healing assay, Co-IP (STIM1-EB1), Ca2+ imaging in Ishikawa cells Biochimica et biophysica acta Medium 25447552
2015 Calsequestrin 1 (CSQ1) interacts with STIM1 in the ER; monomeric CSQ1 induced by store depletion or trifluoperazine enhances CSQ1-STIM1 interaction, which interferes with STIM1 oligomerization and reduces STIM1-Orai1 association and SOCE, providing a brake to SOCE under physiological conditions. Co-immunoprecipitation, pharmacological manipulation of CSQ folding, SOCE measurement, domain deletion mutagenesis in HEK293 cells Scientific reports Medium 26087026
2016 STIM1 has a cholesterol-binding domain located within the SOAR region; STIM1/SOAR associates with cholesterol at the inner plasma membrane leaflet; cholesterol depletion induces SOAR detachment from the plasma membrane and enhances its association with Orai1, modulating SOCE. Cholesterol-binding assay, FRET, Ca2+ imaging, cholesterol depletion, domain mutagenesis Scientific reports Medium 27459950
2011 STIM1 and STIM2 are located in acidic Ca2+ stores (lysosome-related organelles and dense granules) in human platelets; depletion of acidic stores enhances STIM1/STIM2 association with each other and with Orai1, TRPC1, and TRPC6; STIM2-SERCA3 association is also enhanced by acidic store depletion. Immunomagnetic organelle sorting, Co-immunoprecipitation in human platelets The Journal of biological chemistry Medium 21321120
2014 Mitochondrial Ca2+ uptake (via MCU and UCP2) is required for efficient IP3-mediated STIM1 oligomerization; knockdown of MCU or UCP2 decelerated STIM1 oligomerization and impaired SOCE; MCU-dependent mitochondrial Ca2+ sequestration of Ca2+ entering through SOCE is essential to prevent slow deactivation of SOCE. shRNA knockdown of MCU/UCP2, STIM1 oligomerization FRET assay, SOCE measurement in HEK293 cells Journal of cell science Medium 24806964
2019 STIM1 phosphorylation at Y316 regulates SOCE and ICRAC; the Y316F phospho-defective mutant reduces STIM1-Orai1 colocalization, decreases SOCE and ICRAC, alters the pattern of STIM1-SARAF interaction, and enhances slow Ca2+-dependent inactivation (SCDI); Y316 phosphorylation controls the STIM1-SARAF interaction that modulates SCDI. Site-directed mutagenesis, Ca2+ imaging, patch-clamp, Co-IP (STIM1-SARAF), siRNA SARAF knockdown in HEK293 and NG115-401L cells Journal of cell science Medium 30975919
2023 TSPAN18 directly interacts with STIM1 and competitively inhibits E3 ligase TRIM32-mediated ubiquitination and degradation of STIM1, thereby increasing STIM1 protein stability and augmenting SOCE-mediated Ca2+ influx and prostate cancer bone metastasis. Mass spectrometry identification, Co-IP, ubiquitination assay, CRISPR-Cas9 STIM1 knockout, SOCE measurement, in vitro invasion assay, in vivo bone metastasis model Journal of experimental & clinical cancer research : CR Medium 37542345
2009 Phosphatidylinositol 4-phosphate (PtdIns4P) rather than PtdIns(4,5)P2 is a likely determinant of Orai1 channel activity downstream of STIM1; PLC activation or PI4K inhibition substantially reduced SOCE and ICRAC without preventing STIM1 movements toward the PM, indicating that PtdIns4P is required for Orai1 activation but not STIM1 translocation. Chemically induced phosphoinositide 5-phosphatase recruitment, PI4K inhibition, patch-clamp, STIM1 imaging in HEK293 cells The Journal of biological chemistry Medium 19483082
2015 Homer1 mediates the interaction between STIM1 and Cav1.2 voltage-operated Ca2+ channels; store depletion induces co-immunoprecipitation of Homer1 with STIM1 and Cav1.2 α1 subunit; disruption of Homer function reduces STIM1-Cav1.2 association and enhances nifedipine-sensitive Ca2+ entry, indicating Homer1 supports STIM1-mediated suppression of L-type channels. Co-immunoprecipitation, Homer1 siRNA, synthetic Homer-blocking peptide (PPKKFR), Ca2+ imaging in HEK293 cells Biochimica et biophysica acta Medium 25712868
2017 STIM1 promotes phagosomal maturation in dendritic cells by facilitating delivery of endolysosomal enzymes to phagosomes; STIM1 ablation impairs phagosomal proteolysis, leucyl aminopeptidase activity, IRAP recruitment, and phagosome-endosome/lysosome fusion, thereby reducing antigen cross-presentation and DC migration. Conditional STIM1 knockout in myeloid cells, phagosomal pH/ROS assay, proteolysis assay, Ca2+ imaging, chemotaxis assay, cross-presentation assay in bone-marrow-derived DCs Nature communications High 29176619
2010 STIM1 is regulated by the ubiquitin-proteasome system (UPS): STIM1 is ubiquitinated in cells; proteasome inhibition increases surface STIM1 levels and thapsigargin-induced SOCE; E3 ubiquitin ligase POSH overexpression decreases STIM1 surface levels. Surface biotinylation, proteasome inhibition, POSH overexpression, Ca2+ imaging in HEK293 cells and hippocampal neurons PloS one Medium 20976103

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 STIM1, an essential and conserved component of store-operated Ca2+ channel function. The Journal of cell biology 1554 15866891
2009 SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nature cell biology 574 19182790
2006 STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nature cell biology 538 16906149
2015 Diseases caused by mutations in ORAI1 and STIM1. Annals of the New York Academy of Sciences 368 26469693
2014 Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proceedings of the National Academy of Sciences of the United States of America 209 24591628
2010 S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. The Journal of cell biology 202 20679432
2014 A polarized Ca2+, diacylglycerol and STIM1 signalling system regulates directed cell migration. Nature cell biology 200 24463606
2013 Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. The Journal of clinical investigation 195 23348743
2009 TRPC channels function independently of STIM1 and Orai1. The Journal of physiology 186 19332491
2000 STIM1: a novel phosphoprotein located at the cell surface. Biochimica et biophysica acta 186 11004585
2016 TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces. Cell calcium 184 28089266
2008 STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. The Journal of physiology 183 18832420
2007 TRPC channels as STIM1-regulated store-operated channels. Cell calcium 182 17517433
2010 Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Science signaling 171 21081754
2013 STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Archiv : European journal of physiology 164 23515871
2015 Inside-out Ca(2+) signalling prompted by STIM1 conformational switch. Nature communications 158 26184105
2008 Ca2+-store-dependent and -independent reversal of Stim1 localization and function. Journal of cell science 152 18285445
2010 Immunodeficiency due to mutations in ORAI1 and STIM1. Clinical immunology (Orlando, Fla.) 143 20189884
2014 STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion. The Journal of cell biology 138 25404747
2014 A dominant STIM1 mutation causes Stormorken syndrome. Human mutation 135 24619930
2010 Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. Journal of molecular and cellular cardiology 128 20138887
2009 Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. The Journal of biological chemistry 124 19483082
2014 A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). The Journal of biological chemistry 118 25342749
1997 GOK: a gene at 11p15 involved in rhabdomyosarcoma and rhabdoid tumor development. Cancer research 116 9377559
2009 An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS letters 112 19944100
2010 Polarized but differential localization and recruitment of STIM1, Orai1 and TRPC channels in secretory cells. Traffic (Copenhagen, Denmark) 109 21054717
2014 Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochimica et biophysica acta 102 24583265
2011 STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature immunology 101 21441934
2015 STIM1 elevation in the heart results in aberrant Ca²⁺ handling and cardiomyopathy. Journal of molecular and cellular cardiology 96 26241845
2009 TRPC channels as STIM1-regulated SOCs. Channels (Austin, Tex.) 90 19574740
2018 STIM1 activation of Orai1. Cell calcium 87 30530091
2011 Evolutionary origins of STIM1 and STIM2 within ancient Ca2+ signaling systems. Trends in cell biology 87 21288721
2008 STIM1 is essential for Fcgamma receptor activation and autoimmune inflammation. Blood 87 18941110
2015 The STIM1-ORAI1 microdomain. Cell calcium 86 26215475
2016 Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling. Circulation 85 26936863
2008 Interactions, functions, and independence of plasma membrane STIM1 and TRPC1 in vascular smooth muscle cells. Circulation research 79 18802022
2020 STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma. Theranostics 78 32483465
2014 Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. Oncotarget 78 25015419
2013 STIM1 controls endothelial barrier function independently of Orai1 and Ca2+ entry. Science signaling 76 23512989
2014 STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia. Glia 75 25471906
2011 STIM1 and STIM2 are located in the acidic Ca2+ stores and associates with Orai1 upon depletion of the acidic stores in human platelets. The Journal of biological chemistry 73 21321120
2009 Immunolocalization of STIM1 in the mouse brain. Acta neurobiologiae experimentalis 72 20048759
1996 Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5. Genomics 70 8921403
2009 STIM1-independent T cell development and effector function in vivo. Journal of immunology (Baltimore, Md. : 1950) 67 19265116
2018 ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Science signaling 65 30563862
2020 Optogenetic engineering to probe the molecular choreography of STIM1-mediated cell signaling. Nature communications 64 32098964
2018 Calcium sensing by the STIM1 ER-luminal domain. Nature communications 61 30382093
2017 STIM1 and STIM2 cooperatively regulate mouse neutrophil store-operated calcium entry and cytokine production. Blood 60 28724541
2012 Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK. Cell calcium 60 22682960
2017 STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells. Nature communications 55 29176619
2016 Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction. Arteriosclerosis, thrombosis, and vascular biology 55 27470514
2019 Molecular basis of allosteric Orai1 channel activation by STIM1. The Journal of physiology 54 30950063
2013 Suppression of STIM1 inhibits human glioblastoma cell proliferation and induces G0/G1 phase arrest. Journal of experimental & clinical cancer research : CR 54 23578185
2014 IP3-mediated STIM1 oligomerization requires intact mitochondrial Ca2+ uptake. Journal of cell science 53 24806964
2013 Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets. Thrombosis and haemostasis 53 23846758
2017 STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca2+ Entry. Scientific reports 51 28218251
2015 Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proceedings of the National Academy of Sciences of the United States of America 51 26351694
2024 Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis. Pharmacological research 49 38438089
2011 The closing and opening of TRPC channels by Homer1 and STIM1. Acta physiologica (Oxford, England) 49 21518270
2016 A cholesterol-binding domain in STIM1 modulates STIM1-Orai1 physical and functional interactions. Scientific reports 47 27459950
2017 Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers. Nature communications 46 29051492
2015 Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin. Scientific reports 46 26087026
2019 A novel STIM1-Orai1 gating interface essential for CRAC channel activation. Cell calcium 45 30831274
2020 Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions. Frontiers in immunology 43 32038646
2008 Location and function of STIM1 in the activation of Ca2+ entry signals. The Journal of biological chemistry 43 18635545
2010 Regulation of STIM1 and SOCE by the ubiquitin-proteasome system (UPS). PloS one 42 20976103
2009 Physiological function and molecular basis of STIM1-mediated calcium entry in immune cells. Immunological reviews 42 19754897
2017 Role of STIM1 (Stromal Interaction Molecule 1) in Hypertrophy-Related Contractile Dysfunction. Circulation research 41 28592415
2019 Sequential activation of STIM1 links Ca2+ with luminal domain unfolding. Science signaling 40 31744929
2021 A short isoform of STIM1 confers frequency-dependent synaptic enhancement. Cell reports 39 33730587
2014 The TRPCs-STIM1-Orai interaction. Handbook of experimental pharmacology 37 24961979
2020 Interhelical interactions within the STIM1 CC1 domain modulate CRAC channel activation. Nature chemical biology 34 33106661
2012 Surf4 modulates STIM1-dependent calcium entry. Biochemical and biophysical research communications 33 22609200
2014 STIM1 phosphorylation triggered by epidermal growth factor mediates cell migration. Biochimica et biophysica acta 30 25447552
2013 Alternative forms of the store-operated calcium entry mediators, STIM1 and Orai1. Current topics in membranes 30 23890113
2019 STIM1 phosphorylation at Y316 modulates its interaction with SARAF and the activation of SOCE and ICRAC. Journal of cell science 29 30975919
2015 Homer proteins mediate the interaction between STIM1 and Cav1.2 channels. Biochimica et biophysica acta 29 25712868
2023 TSPAN18 facilitates bone metastasis of prostate cancer by protecting STIM1 from TRIM32-mediated ubiquitination. Journal of experimental & clinical cancer research : CR 28 37542345
2022 TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1. The Journal of cell biology 28 35416932
2017 STIM-TRP Pathways and Microdomain Organization: Ca2+ Influx Channels: The Orai-STIM1-TRPC Complexes. Advances in experimental medicine and biology 27 28900913
2010 Ca2+ signaling and STIM1. Progress in biophysics and molecular biology 27 20226808
2018 The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression. Oncotarget 26 30034631
2018 SOCE and STIM1 signaling in the heart: Timing and location matter. Cell calcium 26 30508734
2017 STIM1 silencing inhibits the migration and invasion of A549 cells. Molecular medicine reports 26 28713917
2011 WT1/EGR1-mediated control of STIM1 expression and function in cancer cells. Frontiers in bioscience (Landmark edition) 26 21622185
2023 The SOAR of STIM1 interacts with plasma membrane lipids to form ER-PM contact sites. Cell reports 25 36906853
2022 ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation. Proceedings of the National Academy of Sciences of the United States of America 25 36037373
2021 Desmin interacts with STIM1 and coordinates Ca2+ signaling in skeletal muscle. JCI insight 25 34494555
2017 Regulation of membrane ruffling by polarized STIM1 and ORAI1 in cortactin-rich domains. Scientific reports 25 28341841
2018 STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. Cell calcium 24 30390422
2013 Involvement of STIM1 and Orai1 in EGF-mediated cell growth in retinal pigment epithelial cells. Journal of biomedical science 23 23800047
2013 The regulation of STIM1 by phosphorylation. Communicative & integrative biology 23 24505502
2013 The role of plasma membrane STIM1 and Ca(2+)entry in platelet aggregation. STIM1 binds to novel proteins in human platelets. Cellular signalling 22 24308967
2017 Molecular Determinants for STIM1 Activation During Store- Operated Ca2+ Entry. Current molecular medicine 21 28231751
2017 Stim1 Regulates Enamel Mineralization and Ameloblast Modulation. Journal of dental research 20 28732182
2016 Role of STIM1 in the surface expression of SARAF. Channels (Austin, Tex.) 20 27414851
2022 HSP70 protects H9C2 cells from hypoxia and reoxygenation injury through STIM1/IP3R. Cell stress & chaperones 17 35841499
2020 Stim1 Polymorphism Disrupts Immune Signaling and Creates Renal Injury in Hypertension. Journal of the American Heart Association 17 32075490
2016 Orai1 and STIM1 in ER/PM junctions: roles in pancreatic cell function and dysfunction. American journal of physiology. Cell physiology 17 26739495
2014 STIM1 regulates TRPC6 heteromultimerization and subcellular location. The Biochemical journal 17 25088676