Stim is the single Drosophila stromal interaction molecule, a single-pass endoplasmic reticulum membrane protein that senses ER luminal Ca2+ through an EF-hand/SAM module and activates the plasma membrane CRAC channel formed by Orai. When ER Ca2+ stores are depleted, Stim oligomerises and accumulates at ER-plasma membrane junctions, where its cytosolic C-terminal region binds and gates Orai, driving store-operated Ca2+ entry that refills the ER and sustains cytosolic Ca2+ signals. Stim is essential for larval survival, and its loss affects bristle and wing vein patterning, neuronal Ca2+ signaling required for flight, and presynaptic Ca2+ handling at ER-plasma membrane contacts.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002115 store-operated calcium entry | IBA GO_REF:0000033 | ACCEPT | Summary: Stim is the ER Ca2+ sensor that activates Orai and is required for store-operated Ca2+ entry. Reason: Stim knockdown in S2 cells nearly abolishes SOCE and CRAC current, Stim binds Orai in a store-depletion-enhanced manner, and Stim gates the Orai channel. Stim does part of the work of SOCE (sensing store depletion and gating the channel), so the process annotation is core. Supporting Evidence: PMID:15866891 RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0002115 store-operated calcium entry | IDA PMID:16921385 Molecular identification of the CRAC channel by altered ion ... | ACCEPT | Summary: Stim is the ER Ca2+ sensor that activates Orai and is required for store-operated Ca2+ entry. Reason: Stim knockdown in S2 cells nearly abolishes SOCE and CRAC current, Stim binds Orai in a store-depletion-enhanced manner, and Stim gates the Orai channel. Stim does part of the work of SOCE (sensing store depletion and gating the channel), so the process annotation is core. Supporting Evidence: PMID:15866891 RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0002115 store-operated calcium entry | IEA GO_REF:0000117 | ACCEPT | Summary: Stim is the ER Ca2+ sensor that activates Orai and is required for store-operated Ca2+ entry. Reason: Stim knockdown in S2 cells nearly abolishes SOCE and CRAC current, Stim binds Orai in a store-depletion-enhanced manner, and Stim gates the Orai channel. Stim does part of the work of SOCE (sensing store depletion and gating the channel), so the process annotation is core. Supporting Evidence: PMID:15866891 RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0002115 store-operated calcium entry | IMP PMID:17293345 Biochemical and functional characterization of Orai proteins... | ACCEPT | Summary: Stim is the ER Ca2+ sensor that activates Orai and is required for store-operated Ca2+ entry. Reason: Stim knockdown in S2 cells nearly abolishes SOCE and CRAC current, Stim binds Orai in a store-depletion-enhanced manner, and Stim gates the Orai channel. Stim does part of the work of SOCE (sensing store depletion and gating the channel), so the process annotation is core. Supporting Evidence: PMID:15866891 RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0005246 calcium channel regulator activity | IBA GO_REF:0000033 | ACCEPT | Summary: Stim activates the Orai CRAC channel, i.e. calcium channel regulator activity. Reason: The cytosolic C terminus of Stim binds Orai and is sufficient to activate the channel and drive Orai assembly into the active pore. Calcium channel regulator activity is the appropriate MF; both the IBA and the InterPro (STIM family) mapping are consistent. Supporting Evidence: PMID:18820677 co-expression of GFP-tagged Orai with the carboxy terminus of Stim as a cytosolic protein to activate the Orai channel without inducing Ca(2+) store depletion |
| GO:0005246 calcium channel regulator activity | IEA GO_REF:0000002 | ACCEPT | Summary: Stim activates the Orai CRAC channel, i.e. calcium channel regulator activity. Reason: The cytosolic C terminus of Stim binds Orai and is sufficient to activate the channel and drive Orai assembly into the active pore. Calcium channel regulator activity is the appropriate MF; both the IBA and the InterPro (STIM family) mapping are consistent. Supporting Evidence: PMID:18820677 co-expression of GFP-tagged Orai with the carboxy terminus of Stim as a cytosolic protein to activate the Orai channel without inducing Ca(2+) store depletion |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: Stim binds Ca2+ through its luminal EF-hand, which underlies its sensing of ER Ca2+ content. Reason: The EF-hand Ca2+-binding motif is conserved in Stim and is the basis of its sensor function; the IBA reflects the conserved STIM family property. The cited paper proposes rather than directly measures Ca2+ binding in the text we can see, but the function is clearly correct for the gene family, so the curator is deferred to. Supporting Evidence: PMID:15866891 Its NH2-terminal putative EF-hand Ca2+-binding motif is located outside the cell and, presumably, in the lumen of the ER where it could function as a Ca2+ sensor. |
| GO:0005509 calcium ion binding | IDA PMID:15866891 STIM1, an essential and conserved component of store-operate... | ACCEPT | Summary: Stim binds Ca2+ through its luminal EF-hand, which underlies its sensing of ER Ca2+ content. Reason: The EF-hand Ca2+-binding motif is conserved in Stim and is the basis of its sensor function; the IBA reflects the conserved STIM family property. The cited paper proposes rather than directly measures Ca2+ binding in the text we can see, but the function is clearly correct for the gene family, so the curator is deferred to. Supporting Evidence: PMID:15866891 Its NH2-terminal putative EF-hand Ca2+-binding motif is located outside the cell and, presumably, in the lumen of the ER where it could function as a Ca2+ sensor. |
| GO:0005513 detection of calcium ion | IDA PMID:15866891 STIM1, an essential and conserved component of store-operate... | ACCEPT | Summary: Stim detects ER luminal Ca2+ levels. Reason: Sensing of store Ca2+ is the defining activity of Stim and it is directly involved in detecting Ca2+ depletion. Supporting Evidence: PMID:15866891 STIM1 might function as a Ca2+ sensor or a coupler linking store depletion to activation of SOC influx channels |
| GO:0005515 protein binding | IPI PMID:16921385 Molecular identification of the CRAC channel by altered ion ... | REMOVE | Summary: Stim co-immunoprecipitates with Orai, especially after store depletion. Reason: The interaction is real and is the mechanism by which Stim gates Orai, but protein binding is uninformative; the functional content is captured by calcium channel regulator activity. Supporting Evidence: PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0005515 protein binding | IPI PMID:18820677 The CRAC channel consists of a tetramer formed by Stim-induc... | REMOVE | Summary: Stim co-immunoprecipitates with Orai, especially after store depletion. Reason: The interaction is real and is the mechanism by which Stim gates Orai, but protein binding is uninformative; the functional content is captured by calcium channel regulator activity. Supporting Evidence: PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Stim resides in the ER. Reason: Stim is an ER membrane protein whose luminal domain senses store Ca2+. Supporting Evidence: PMID:18820677 Stim senses depletion of the ER Ca(2+) store and physically relays this information by translocating from the ER to junctions adjacent to the plasma membrane |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-DME-434702 | ACCEPT | Summary: Reactome places Stim in the ER membrane during CRAC activation. Reason: Correct; ER membrane is the primary location of Stim. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-DME-434802 | ACCEPT | Summary: Reactome places Stim in the ER membrane during CRAC activation. Reason: Correct; ER membrane is the primary location of Stim. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Plasma membrane localisation for Stim. Reason: Stim acts mainly from the ER membrane at ER-plasma membrane junctions, where it contacts Orai in the plasma membrane; the Zhang et al. model of Stim translocating "to the plasma membrane" reflects accumulation at ER-PM junctions. A minor surface pool is described for mammalian STIM1 and is the basis of the family-level IBA, but there is no Drosophila evidence that Stim functions as a plasma membrane resident protein. ER membrane and ER-PM contact site are the informative locations; the plasma membrane rows are retained as non-core. Supporting Evidence: PMID:18820677 translocating from the ER to junctions adjacent to the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Plasma membrane localisation for Stim. Reason: Stim acts mainly from the ER membrane at ER-plasma membrane junctions, where it contacts Orai in the plasma membrane; the Zhang et al. model of Stim translocating "to the plasma membrane" reflects accumulation at ER-PM junctions. A minor surface pool is described for mammalian STIM1 and is the basis of the family-level IBA, but there is no Drosophila evidence that Stim functions as a plasma membrane resident protein. ER membrane and ER-PM contact site are the informative locations; the plasma membrane rows are retained as non-core. Supporting Evidence: PMID:18820677 translocating from the ER to junctions adjacent to the plasma membrane |
| GO:0005886 plasma membrane | NAS PMID:16751269 Genome-wide RNAi screen of Ca(2+) influx identifies genes th... | KEEP AS NON CORE | Summary: Plasma membrane localisation for Stim. Reason: Stim acts mainly from the ER membrane at ER-plasma membrane junctions, where it contacts Orai in the plasma membrane; the Zhang et al. model of Stim translocating "to the plasma membrane" reflects accumulation at ER-PM junctions. A minor surface pool is described for mammalian STIM1 and is the basis of the family-level IBA, but there is no Drosophila evidence that Stim functions as a plasma membrane resident protein. ER membrane and ER-PM contact site are the informative locations; the plasma membrane rows are retained as non-core. Supporting Evidence: PMID:18820677 translocating from the ER to junctions adjacent to the plasma membrane |
| GO:0006874 intracellular calcium ion homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Stim contributes to intracellular calcium ion homeostasis by refilling ER stores via SOCE. Reason: SOCE is a homeostatic mechanism for ER Ca2+ store refilling; consistent IBA. SOCE is the more specific process. Supporting Evidence: PMID:19515818 replenishment of intracellular store Ca(2+) in neurons is required for Drosophila flight |
| GO:0007476 imaginal disc-derived wing morphogenesis | IMP PMID:18950512 The Drosophila STIM1 orthologue, dSTIM, has roles in cell fa... | KEEP AS NON CORE | Summary: dSTIM knockdown/overexpression alters wing vein thickness and notum bristle specification. Reason: These are tissue-level developmental phenotypes downstream of Ca2+ signaling, plausibly via Notch/Wingless interactions, rather than processes Stim executes directly. Supporting Evidence: PMID:18950512 a tissue-specific role in cell fate specification of mechanosensory bristles in the notum and in specification of wing vein thickness |
| GO:0012505 endomembrane system | HDA PMID:19317464 Mapping organelle proteins and protein complexes in Drosophi... | MODIFY | Summary: LOPIT proteomics places Stim in the endomembrane system. Reason: Consistent with ER residence; correct but general, so MODIFY to endoplasmic reticulum membrane, which Stim already carries (TAS). Proposed replacements: endoplasmic reticulum membrane |
| GO:0016020 membrane | NAS PMID:15866891 STIM1, an essential and conserved component of store-operate... | MODIFY | Summary: Stim is a membrane protein. Reason: Correct but general; Stim is a single-pass ER membrane protein, so MODIFY to endoplasmic reticulum membrane, which Stim already carries (TAS). Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:15866891 Its NH2-terminal putative EF-hand Ca2+-binding motif is located outside the cell and, presumably, in the lumen of the ER |
| GO:0022416 chaeta development | IMP PMID:18950512 The Drosophila STIM1 orthologue, dSTIM, has roles in cell fa... | KEEP AS NON CORE | Summary: dSTIM knockdown/overexpression alters wing vein thickness and notum bristle specification. Reason: These are tissue-level developmental phenotypes downstream of Ca2+ signaling, plausibly via Notch/Wingless interactions, rather than processes Stim executes directly. Supporting Evidence: PMID:18950512 a tissue-specific role in cell fate specification of mechanosensory bristles in the notum and in specification of wing vein thickness |
| GO:0034704 calcium channel complex | IPI PMID:16921385 Molecular identification of the CRAC channel by altered ion ... | ACCEPT | Summary: Stim associates with Orai in the CRAC channel complex. Reason: Stim co-immunoprecipitates with Orai and is the activating subunit of the functional Stim-Orai CRAC channel assembly. Supporting Evidence: PMID:16921385 interaction between wild-type Stim and Orai, assessed by co-immunoprecipitation, is greatly enhanced after treatment with thapsigargin to induce Ca2+ store depletion |
| GO:0051924 regulation of calcium ion transport | IDA PMID:15866891 STIM1, an essential and conserved component of store-operate... | MODIFY | Summary: Stim regulates Ca2+ transport by activating CRAC channels. Reason: Correct but general; Stim specifically activates the store-operated Orai channel, which is captured by activation of store-operated calcium channel activity (as annotated to human STIM1). Proposed replacements: activation of store-operated calcium channel activity Supporting Evidence: PMID:15866891 Patch-clamp recording revealed nearly complete suppression of the Drosophila Ca2+ release-activated Ca2+ (CRAC) current |
| GO:0061891 calcium ion sensor activity | IMP PMID:15866891 STIM1, an essential and conserved component of store-operate... | ACCEPT | Summary: Stim acts as an ER Ca2+ sensor. Reason: Calcium ion sensor activity describes the core Stim activity of sensing luminal Ca2+ and transducing store depletion into Orai activation. Supporting Evidence: PMID:15866891 Its NH2-terminal putative EF-hand Ca2+-binding motif is located outside the cell and, presumably, in the lumen of the ER where it could function as a Ca2+ sensor. |
| GO:0140268 endoplasmic reticulum-plasma membrane contact site | IDA PMID:36952540 Drosophila SPG12 ortholog, reticulon-like 1, governs presyna... | ACCEPT | Summary: STIM-mediated ER-PM contacts at presynaptic terminals. Reason: Stim accumulates at ER-plasma membrane contacts where it gates Orai; the Rtnl1 study shows reduced STIM-mediated ER-PM contacts in Drosophila presynaptic terminals. Supporting Evidence: PMID:36952540 We found that reduced STIM-mediated ER-plasma membrane contacts underlie presynaptic Ca2+ defects in Rtnl1 mutants. |
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Download this section (compressed HTML)Q: Does Drosophila Stim have a functional plasma membrane pool, as reported for mammalian STIM1, or does it act exclusively from the ER at ER-PM junctions?
Q: Are the bristle and wing vein phenotypes of dSTIM perturbation mediated through Orai-dependent SOCE or through SOCE-independent roles?
Experiment: Compare Stim RNAi phenotypes with Orai dominant-negative (E180A) expression and test rescue by a gating-defective Stim SOAR mutant in the same tissues.
Hypothesis: Stim developmental phenotypes in the notum and wing require Orai channel gating.
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Download this section (compressed HTML)Stromal interaction molecule (Stim) encodes an endomasplic reticulum-membrane protein that is an essential component of the store-operated calcium entry mechanism, which in neurons regulates flight.
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