Stxbp1 encodes Munc18-1 (nSec1, rbSec1), the neuronal Sec1/Munc18 (SM) protein of the STXBP/unc-18/SEC1 family. It is a soluble cytosolic protein that associates peripherally with the plasma membrane by binding the t-SNARE syntaxin-1. Munc18-1 binds syntaxin-1 in two modes: tightly to its closed conformation, a binary complex that chaperones and stabilizes syntaxin-1 and blocks premature SNARE assembly, and through the syntaxin N-peptide to syntaxin-1/SNAP-25 acceptor complexes and assembled SNARE complexes. After Munc13 opens syntaxin-1, domain 3a of Munc18-1 binds VAMP2 and acts as a template that aligns syntaxin-1 and VAMP2 and accelerates trans-SNARE complex assembly and membrane fusion. In neurons it is essential for synaptic vesicle priming and neurotransmitter release; in neuroendocrine cells (PC12, chromaffin) it is required for docking and Ca2+-triggered exocytosis of dense-core vesicles, and its syntaxin N-peptide interaction raises vesicle fusion probability. It also contributes to regulated exocytosis in mast cells and the sperm acrosome. Other reported partners include Mint1/2, Cdk5, phospholipase D and Rab3A.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000149 SNARE binding | IDA PMID:18201107 Binding of the Munc13-1 MUN domain to membrane-anchored SNAR... | ACCEPT | Summary: Munc18-1 binds membrane-anchored syntaxin-1/SNAP-25 heterodimers and SNARE complexes. Reason: SNARE binding covers the full range of Munc18-1 SNARE partners (closed syntaxin-1, syntaxin-1/SNAP-25 acceptor complexes, assembled SNARE complexes and VAMP2); it is the appropriate level for complex-directed binding. Core activity. Supporting Evidence: PMID:18201107 our data also uncover interactions of membrane-anchored syntaxin-1/SNAP-25 heterodimers with the MUN domain, Munc18-1 and complexin-1 PMID:17301226 We now show that Munc18-1 also binds tightly to assembled SNARE complexes containing syntaxin-1 |
| GO:0000149 SNARE binding | IDA PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | ACCEPT | Summary: Munc18-1 binds closed syntaxin-1 and assembled SNARE complexes (full text read). Reason: Deak et al. map distinct binding modes to closed syntaxin-1 and to SNARE complexes containing open syntaxin-1; SNARE binding is the precise term for complex binding. Core activity. Supporting Evidence: PMID:19255244 Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1 PMID:19255244 These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1-SNARE-complexin macromolecular assembly that is poised for Ca(2+) triggering of fusion |
| GO:0000149 SNARE binding | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic SNARE binding agrees with the experimental evidence. Reason: Consistent with direct experimental demonstration of binding to syntaxin-1 and SNARE complexes; core activity. Supporting Evidence: PMID:17301226 We now show that Munc18-1 also binds tightly to assembled SNARE complexes containing syntaxin-1 PMID:24532794 A single point mutation (L348R) within helix 12 selectively abolishes VAMP2 binding and the stimulatory function of Munc18-1 in membrane fusion |
| GO:0000149 SNARE binding | IMP PMID:15563604 Munc18-1 regulates early and late stages of exocytosis via s... | ACCEPT | Summary: Mutants with reduced syntaxin-1A binding were characterised in chromaffin cells. Reason: Mutational analysis of Munc18-1 SNARE (syntaxin-1A) binding; the binding claim is well supported by the structural and biochemical literature. Core activity. Supporting Evidence: PMID:15563604 Munc18-1 controls multiple stages of exocytosis via both syntaxin-dependent and -independent protein interactions PMID:10746715 Syntaxin 1a and neuronal Sec1 (nSec1) form an evolutionarily conserved heterodimer that is essential for vesicle trafficking and membrane fusion |
| GO:0002576 platelet degranulation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Platelet degranulation inferred from human Munc18 peptide-inhibition data in which Munc18c dominates. Reason: The human source (PMID:12773094) used Munc18a/Munc18c-derived peptides in permeabilized platelets; the authors conclude Munc18c has the dominant role. A role for Munc18-1 specifically in platelet degranulation is not established. Supporting Evidence: PMID:12773094 suggest a dominant role for Munc18c in all three granule-release events PMID:12773094 Three Sec1/Munc18 proteins (SM proteins) are present in platelets (Munc18a, Munc18b and Munc18c) |
| GO:0002576 platelet degranulation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Platelet degranulation inferred from human Munc18 peptide-inhibition data in which Munc18c dominates. Reason: The human source (PMID:12773094) used Munc18a/Munc18c-derived peptides in permeabilized platelets; the authors conclude Munc18c has the dominant role. A role for Munc18-1 specifically in platelet degranulation is not established. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK WRONG ORTHOLOG OR PARALOG Sources checked: UniProtKB:P61764 SOURCE WEAK OR INFERRED Human IMP (PMID:12773094) used Munc18 peptides; dominant SM protein is Munc18c. Supporting Evidence: PMID:12773094 suggest a dominant role for Munc18c in all three granule-release events PMID:12773094 Three Sec1/Munc18 proteins (SM proteins) are present in platelets (Munc18a, Munc18b and Munc18c) |
| GO:0003006 developmental process involved in reproduction | IMP PMID:16951547 Munc18 plays an important role in the regulation of glutamat... | MARK AS OVER ANNOTATED | Summary: Delayed puberty after hypothalamic antisense knockdown is an indirect systemic consequence of reduced glutamate release. Reason: Munc18-1 is needed for neurotransmitter release; puberty timing is a downstream organismal outcome, not a process the protein performs. Abstract-only, so not removed. Supporting Evidence: PMID:16951547 Intracerebroventricular administration of an antisense oligodeoxynucleotide against munc18-1 mRNA significantly decreased glutamate release and delayed the day of puberty onset |
| GO:0005515 protein binding | IPI PMID:10746715 Three-dimensional structure of the neuronal-Sec1-syntaxin 1a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:12093152 Munc 18a binding to syntaxin 1A and 1B isoforms defines its ... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:12093152 Munc 18a binding to syntaxin 1A and 1B isoforms defines its ... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17301226 Munc18-1 binds directly to the neuronal SNARE complex. | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:18337752 Munc18a controls SNARE assembly through its interaction with... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:21193638 Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptid... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:21193638 Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptid... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:21689256 Involvement of Rab3A in vesicle priming during exocytosis: i... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:26359495 The Q-soluble N-Ethylmaleimide-sensitive Factor Attachment P... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:26876096 Munc18-1 and the Syntaxin-1 N Terminus Regulate Open-Closed ... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:9395480 Mints, Munc18-interacting proteins in synaptic vesicle exocy... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005515 protein binding | IPI PMID:9395480 Mints, Munc18-interacting proteins in synaptic vesicle exocy... | REMOVE | Summary: Bare protein binding is uninformative. Reason: Per the protein-binding policy GO:0005515 is removed; the informative partner interactions (syntaxin-1, SNARE complexes, Mints, Cdk5, PLD, Rab3A) are captured by SNARE binding, syntaxin-1 binding, protein kinase binding and phospholipase binding rows. |
| GO:0005737 cytoplasm | IDA PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | MODIFY | Summary: Munc18-1 is a soluble cytosolic protein recruited to membranes; cytosol is the precise compartment. Reason: Cytoplasm is correct but general; the gene already carries cytosol (GO:0005829), which is where the soluble pool resides before syntaxin-dependent plasma-membrane recruitment. Proposed replacements: cytosol Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | MODIFY | Summary: Electronic cytoplasm; refine to cytosol. Reason: Cytoplasm is correct but general; the gene already carries cytosol (GO:0005829), which is where the soluble pool resides before syntaxin-dependent plasma-membrane recruitment. Proposed replacements: cytosol Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Soluble cytosolic pool of Munc18-1. Reason: Munc18-1 is a peripheral membrane protein with a cytosolic pool; consistent with Reactome and with syntaxin-dependent membrane recruitment. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. Reactome:R-RNO-6794339 MUNC18, a sec1-like protein that is essential for neurotransmitter release exists in complex with Syntaxin (STX1A) and MINT1 and MINT2 in the nervous system |
| GO:0005829 cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Soluble cytosolic pool of Munc18-1. Reason: Munc18-1 is a peripheral membrane protein with a cytosolic pool; consistent with Reactome and with syntaxin-dependent membrane recruitment. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. Reactome:R-RNO-6794339 MUNC18, a sec1-like protein that is essential for neurotransmitter release exists in complex with Syntaxin (STX1A) and MINT1 and MINT2 in the nervous system |
| GO:0005829 cytosol | TAS Reactome:R-RNO-6794339 | ACCEPT | Summary: Reactome places Munc18-1 in the cytosol in complex with Mints and syntaxin. Reason: Consistent with its soluble, peripheral-membrane character. Supporting Evidence: Reactome:R-RNO-6794339 MUNC18, a sec1-like protein that is essential for neurotransmitter release exists in complex with Syntaxin (STX1A) and MINT1 and MINT2 in the nervous system file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. |
| GO:0005886 plasma membrane | IDA PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | ACCEPT | Summary: Munc18 colocalizes with syntaxin at the plasma membrane. Reason: Munc18-1 is recruited to the plasma membrane by syntaxin-1, where it acts on SNAREs; colocalizes_with is appropriate. Supporting Evidence: PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Plasma membrane (cytoplasmic face) via syntaxin binding. Reason: Supported by syntaxin-dependent plasma membrane localization and single-molecule imaging at the plasma membrane. Supporting Evidence: PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane PMID:20801887 We conclude that the presence of munc18 molecules, engaged in regulated mode 2/3 interaction with syntaxin, exerts a strong positive effect on a specific postdocking pool of vesicles, increasing the probability of fusion by a factor of 5 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane (cytoplasmic face) via syntaxin binding. Reason: Supported by syntaxin-dependent plasma membrane localization and single-molecule imaging at the plasma membrane. Supporting Evidence: PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane PMID:20801887 We conclude that the presence of munc18 molecules, engaged in regulated mode 2/3 interaction with syntaxin, exerts a strong positive effect on a specific postdocking pool of vesicles, increasing the probability of fusion by a factor of 5 |
| GO:0005886 plasma membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Plasma membrane (cytoplasmic face) via syntaxin binding. Reason: Supported by syntaxin-dependent plasma membrane localization and single-molecule imaging at the plasma membrane. Supporting Evidence: PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane PMID:20801887 We conclude that the presence of munc18 molecules, engaged in regulated mode 2/3 interaction with syntaxin, exerts a strong positive effect on a specific postdocking pool of vesicles, increasing the probability of fusion by a factor of 5 |
| GO:0006886 intracellular protein transport | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Family-level protein transport term from vacuolar/endosomal SM proteins; Munc18-1 acts in exocytosis. Reason: The IBA node is seeded by Vps45/Vps33-type SM proteins (AT1G77140, FBgn0000257 car, MGI:2446237) that act in endosomal/vacuolar trafficking. Munc18-1's only transport-related role is chaperoning syntaxin-1 delivery to the plasma membrane, better captured by protein localization to plasma membrane. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: AGI_LocusCode:AT1G77140 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. FB:FBgn0000257 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. MGI:MGI:2446237 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. PANTHER:PTN000187655 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. SGD:S000003063 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. SGD:S000004388 SUPPORTS SOURCE BUT NOT TARGET Vps45/Vps33-type SM function in endosomal/vacuolar trafficking does not transfer to Munc18-1. Supporting Evidence: PMID:17543282 Munc18-1 is found not to be essential for Stx1A cluster distribution, despite important role in stabilizing membrane delivery of Stx1A PMID:26359495 with syntaxin 1 in the absence of Munc18a, when syntaxin 1 is retained in the ER |
| GO:0006887 exocytosis | IEA GO_REF:0000117 | MODIFY | Summary: Exocytosis is correct but general; Munc18-1 executes synaptic vesicle and dense-core vesicle exocytosis. Reason: Refine to the specific regulated exocytosis processes it is shown to perform: synaptic vesicle exocytosis (neurons) and dense core granule exocytosis (PC12/chromaffin; gene already carries GO:1990504). Proposed replacements: synaptic vesicle exocytosis dense core granule exocytosis Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 |
| GO:0006887 exocytosis | IMP PMID:15563604 Munc18-1 regulates early and late stages of exocytosis via s... | MODIFY | Summary: Chromaffin-cell exocytosis is dense-core granule exocytosis. Reason: The assay measured large dense-core vesicle exocytosis in adrenal chromaffin cells; the specific term GO:1990504 is already on the gene. Proposed replacements: dense core granule exocytosis Supporting Evidence: PMID:15563604 Expression of these mutants in chromaffin cells either increased the rate and extent of exocytosis or altered the kinetics of individual release events |
| GO:0006887 exocytosis | ISO GO_REF:0000121 | MODIFY | Summary: Mouse knockout chromaffin-cell exocytosis defect; refine to dense core granule exocytosis. Reason: The mouse donor (PMID:11545717) is the chromaffin large dense-core vesicle phenotype; GO:1990504 is the specific process. Rat PC12 data agree. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:107363 SUPPORTS TRANSFER Mouse chromaffin dense-core vesicle phenotype; sound but general. Proposed replacements: dense core granule exocytosis Supporting Evidence: PMID:20801887 In the absence of munc18, stimulated exocytosis was not significantly different from basal secretion PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 |
| GO:0007269 neurotransmitter secretion | IEA GO_REF:0000117 | ACCEPT | Summary: Munc18-1 is essential for neurotransmitter secretion. Reason: Knockout abolishes release and lentiviral Munc18-1 rescues it; core process. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes |
| GO:0007269 neurotransmitter secretion | ISO GO_REF:0000121 | ACCEPT | Summary: Munc18-1 is essential for neurotransmitter secretion. Reason: Knockout abolishes release and lentiviral Munc18-1 rescues it; core process. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes |
| GO:0007274 neuromuscular synaptic transmission | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Knockout abolishes synaptic transmission including at the neuromuscular junction. Reason: A consequence of its general requirement for synaptic vesicle exocytosis; synapse-type specific term is peripheral. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0007412 axon target recognition | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Axon targeting defects in knockout mice are secondary to loss of release. Reason: Munc18-1 does not perform axon target recognition; knockout phenotypes in circuit wiring reflect absence of neurotransmission and neurodegeneration. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Mouse knockout phenotype secondary to loss of release. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0010807 regulation of synaptic vesicle priming | IDA PMID:21689256 Involvement of Rab3A in vesicle priming during exocytosis: i... | MODIFY | Summary: In PC12 cells Munc18-1 acts downstream of Rab3A/Munc13-1 and binds syntaxin to allow vesicle priming. Reason: Munc18-1 is a component of the priming machinery rather than a modulator, and PC12 secretory vesicles are dense-core vesicles; dense core granule priming (GO:0061789) is the correct process. Proposed replacements: dense core granule priming Supporting Evidence: PMID:21689256 Munc18-1 acts downstream of Munc13-1/RIM/Rab3A and interacts with syntaxin 1a allowing vesicle priming |
| GO:0010807 regulation of synaptic vesicle priming | IMP PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | MODIFY | Summary: Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming (full text read). Reason: Deak et al. show that Munc18-1/SNARE-complex binding mutants selectively impair priming; Munc18-1 executes priming, so synaptic vesicle priming (GO:0016082, already on the gene) is more accurate than regulation of priming. Proposed replacements: synaptic vesicle priming Supporting Evidence: PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles PMID:19255244 These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1-SNARE-complexin macromolecular assembly that is poised for Ca(2+) triggering of fusion |
| GO:0010808 positive regulation of synaptic vesicle priming | IMP PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | MODIFY | Summary: Same evidence as the regulation row; Munc18-1 is part of the priming process. Reason: Deak et al. show that Munc18-1/SNARE-complex binding mutants selectively impair priming; Munc18-1 executes priming, so synaptic vesicle priming (GO:0016082, already on the gene) is more accurate than regulation of priming. Proposed replacements: synaptic vesicle priming Supporting Evidence: PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles PMID:19255244 These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1-SNARE-complexin macromolecular assembly that is poised for Ca(2+) triggering of fusion |
| GO:0016020 membrane | IEA GO_REF:0000044 | MODIFY | Summary: Peripheral membrane protein; the membrane is the plasma membrane. Reason: Membrane is correct but general; Munc18-1 associates with the plasma membrane via syntaxin-1 (gene carries GO:0005886). Proposed replacements: plasma membrane Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0016082 synaptic vesicle priming | ISO GO_REF:0000121 | ACCEPT | Summary: Synaptic vesicle priming is a core process of Munc18-1. Reason: Supported directly in rat-protein rescue experiments in Munc18-1 KO neurons. Supporting Evidence: PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles PMID:19255244 These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1-SNARE-complexin macromolecular assembly that is poised for Ca(2+) triggering of fusion |
| GO:0016188 synaptic vesicle maturation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Synaptic vesicle maturation is not a process Munc18-1 is shown to perform. Reason: Munc18-1 acts at docking/priming/fusion of mature vesicles; a vesicle biogenesis/maturation role rests on an indirect knockout phenotype. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Mouse knockout phenotype; no direct role in vesicle maturation. Supporting Evidence: PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000002 | MODIFY | Summary: Vesicle-mediated transport is correct but very general. Reason: Refine to the exocytic vesicle-transport processes Munc18-1 performs. Proposed replacements: synaptic vesicle exocytosis dense core granule exocytosis Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 |
| GO:0016192 vesicle-mediated transport | IGI PMID:15563604 Munc18-1 regulates early and late stages of exocytosis via s... | MODIFY | Summary: Chromaffin exocytosis evidence; refine to dense core granule exocytosis. Reason: The assay measured chromaffin dense-core vesicle exocytosis. Proposed replacements: dense core granule exocytosis Supporting Evidence: PMID:15563604 Expression of these mutants in chromaffin cells either increased the rate and extent of exocytosis or altered the kinetics of individual release events |
| GO:0017075 syntaxin-1 binding | IBA GO_REF:0000033 | ACCEPT | Summary: Syntaxin-1 binding is the defining activity of Munc18-1. Reason: Crystal structures and binding studies show high-affinity binding to closed syntaxin-1 and its N-peptide; inherited across the Munc18-1 clade. Supporting Evidence: PMID:10746715 Syntaxin 1a and neuronal Sec1 (nSec1) form an evolutionarily conserved heterodimer that is essential for vesicle trafficking and membrane fusion PMID:12093152 Munc-18a significantly binds both isoforms of syntaxin 1 (syntaxins 1A and 1B) |
| GO:0017075 syntaxin-1 binding | IDA PMID:7553862 Complexins: cytosolic proteins that regulate SNAP receptor f... | ACCEPT | Summary: Syntaxin-1 binding. Reason: Curated IDA; the activity is established by many independent studies (structure, binding assays). Supporting Evidence: PMID:10746715 Syntaxin 1a and neuronal Sec1 (nSec1) form an evolutionarily conserved heterodimer that is essential for vesicle trafficking and membrane fusion PMID:12093152 Munc-18a significantly binds both isoforms of syntaxin 1 (syntaxins 1A and 1B) PMID:18337752 When the syntaxin 1a N-peptide is bound to Munc18a, SNARE complex formation is blocked |
| GO:0019901 protein kinase binding | IPI PMID:12963086 Co-purification and localization of Munc18-1 (p67) and Cdk5 ... | KEEP AS NON CORE | Summary: Munc18-1 co-purifies with Cdk5. Reason: Interaction with Cdk5 is reported but peripheral to the SNARE function. Supporting Evidence: PMID:12963086 the cytoskeletal proteins and Cdk5 co-purifies with Munc18-1 in a Munc18-1 immuno-affinity chromatography |
| GO:0019904 protein domain specific binding | IDA PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | MODIFY | Summary: Binding to the syntaxin-1 N-terminal region; express as syntaxin-1 binding. Reason: Protein domain specific binding is uninformative; the domain bound is the syntaxin-1 N-terminal region (Habc/N-peptide), so syntaxin-1 binding (GO:0017075) states the claim. Proposed replacements: syntaxin-1 binding Supporting Evidence: PMID:19255244 Munc18-1 binds to the SNARE syntaxin-1 folded into a closed conformation and to SNARE complexes containing open syntaxin-1 |
| GO:0030141 secretory granule | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Munc18-1 acts at the plasma membrane, not on secretory granules. Reason: The IBA is seeded by Munc18b/c-type paralogs (Stxbp3, MGI:107370) that associate with granules in platelets; Munc18-1 is a cytosolic protein recruited to plasma-membrane syntaxin-1. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: MGI:MGI:107370 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. PANTHER:PTN000187656 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. RGD:619967 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. UniProtKB:O00186 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. UniProtKB:P61764 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. UniProtKB:Q15833 SUPPORTS SOURCE BUT NOT TARGET Granule association holds for Munc18b/c paralogs, not Munc18-1. Supporting Evidence: PMID:12773094 In resting platelets, these SM proteins associate with granules and open canalicular system membranes predominantly but not with the plasma membrane PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0030424 axon | IDA PMID:15869823 Nuclear localization of Munc18-1 (p67) in the adult rat brai... | KEEP AS NON CORE | Summary: Munc18-1 is enriched in axons. Reason: Correct localization but not where the core activity is executed (presynaptic terminal). Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Brain and spinal cord. Highly enriched in axons. |
| GO:0030424 axon | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Munc18-1 is enriched in axons. Reason: Correct localization but not where the core activity is executed (presynaptic terminal). Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Brain and spinal cord. Highly enriched in axons. |
| GO:0031091 platelet alpha granule | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Human Munc18a detected in platelet alpha granule fractions. Reason: Platelet localization is a peripheral, non-neuronal context. Supporting Evidence: PMID:12773094 In resting platelets, these SM proteins associate with granules and open canalicular system membranes predominantly but not with the plasma membrane |
| GO:0031091 platelet alpha granule | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Human Munc18a detected in platelet alpha granule fractions. Reason: Platelet localization is a peripheral, non-neuronal context. Supporting Evidence: PMID:12773094 In resting platelets, these SM proteins associate with granules and open canalicular system membranes predominantly but not with the plasma membrane |
| GO:0031333 negative regulation of protein-containing complex assembly | IDA PMID:12093152 Munc 18a binding to syntaxin 1A and 1B isoforms defines its ... | MODIFY | Summary: Munc18a inhibits syntaxin-1/VAMP complex formation; the complex is a SNARE complex. Reason: Refine to negative regulation of SNARE complex assembly (GO:0035544), already on the gene. Proposed replacements: negative regulation of SNARE complex assembly Supporting Evidence: PMID:12093152 we showed the inhibitory role of Munc-18a in the formation of syntaxin 1-synaptobrevin/VAMP complexes regardless of the isoforms PMID:18337752 When the syntaxin 1a N-peptide is bound to Munc18a, SNARE complex formation is blocked |
| GO:0031338 regulation of vesicle fusion | IDA PMID:24532794 An extended helical conformation in domain 3a of Munc18-1 pr... | MODIFY | Summary: Munc18-1 helix 12 stimulates SNAREpin assembly and fusion (full text read). Reason: The data show a stimulatory effect; positive regulation of vesicle fusion (GO:0031340, on the gene) states the direction. Proposed replacements: positive regulation of vesicle fusion Supporting Evidence: PMID:24532794 we show that helix 12 in domain 3a of Munc18-1 stimulates SNAREpin assembly and membrane fusion PMID:24532794 A single point mutation (L348R) within helix 12 selectively abolishes VAMP2 binding and the stimulatory function of Munc18-1 in membrane fusion |
| GO:0031340 positive regulation of vesicle fusion | IMP PMID:26030875 Syntaxin opening by the MUN domain underlies the function of... | KEEP AS NON CORE | Summary: In vitro, fusion reactions starting from the Munc18-1/syntaxin-1 complex require the MUN domain. Reason: Munc18-1 is a component of the reconstituted fusion machinery that accelerates SNARE-mediated fusion; regulation of fusion is a valid but peripheral framing of its template role. Supporting Evidence: PMID:26030875 Munc18-1 strongly inhibits SNARE complex formation, whereas addition of either MUN* or MUN933 equally facilitates SNARE complex assembly PMID:24532794 we show that helix 12 in domain 3a of Munc18-1 stimulates SNAREpin assembly and membrane fusion |
| GO:0031629 synaptic vesicle fusion to presynaptic active zone membrane | IDA PMID:22810233 SNAREpin assembly by Munc18-1 requires previous vesicle dock... | ACCEPT | Summary: Munc18-1 is part of the minimal SNARE/SM fusion machinery. Reason: Reconstitution shows Munc18-1 accelerates SNAREpin assembly and fusion; in neurons this is synaptic vesicle fusion. Supporting Evidence: PMID:22810233 vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion PMID:24532794 we show that helix 12 in domain 3a of Munc18-1 stimulates SNAREpin assembly and membrane fusion |
| GO:0032229 negative regulation of synaptic transmission, GABAergic | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Negative regulation of GABAergic transmission conflicts with the requirement of Munc18-1 for release. Reason: Munc18-1 is required for both glutamatergic and GABAergic release; a negative-regulatory role from a mouse dosage study is not a process the protein performs. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: REGULATORY SIGN INVERSION ROLE CONFLATION Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Mouse phenotype; Munc18-1 is required for GABA release. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0032355 response to estradiol | IEP PMID:16951547 Munc18 plays an important role in the regulation of glutamat... | KEEP AS NON CORE | Summary: Hypothalamic Munc18-1 mRNA rises with estrogen. Reason: Expression response (IEP) is valid but peripheral. Supporting Evidence: PMID:16951547 Hypothalamic munc18-1 mRNA levels were significantly increased by estrogen treatment in ovariectomized, immature female rats |
| GO:0032991 protein-containing complex | IDA PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | KEEP AS NON CORE | Summary: Munc18-1 forms a Munc18-1-SNARE-complexin assembly. Reason: Correct; no more specific CC term captures the SM/SNARE acceptor assembly. Supporting Evidence: PMID:19255244 These results suggest that Munc18-1 binding to SNARE complexes mediates synaptic vesicle priming and that the resulting primed state involves a Munc18-1-SNARE-complexin macromolecular assembly that is poised for Ca(2+) triggering of fusion |
| GO:0035493 SNARE complex assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Munc18-1 templates SNARE complex assembly. Reason: Core process; supported by reconstitution and human sperm data. Supporting Evidence: PMID:24532794 the data suggest that helix 12 provides a folding template for VAMP2, accelerating SNAREpin assembly and membrane fusion file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes PMID:23091057 our results indicate that Munc18-1 plays a key role in the dynamics of trans-SNARE complex assembly and/or stabilization file:rat/Stxbp1/Stxbp1-deep-research-manual.md Munc18-1 domain 3a helix 12 templates VAMP2 and syntaxin, accelerating |
| GO:0035493 SNARE complex assembly | ISO GO_REF:0000121 | ACCEPT | Summary: Munc18-1 templates SNARE complex assembly. Reason: Core process; supported by reconstitution and human sperm data. Supporting Evidence: PMID:24532794 the data suggest that helix 12 provides a folding template for VAMP2, accelerating SNAREpin assembly and membrane fusion file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes PMID:23091057 our results indicate that Munc18-1 plays a key role in the dynamics of trans-SNARE complex assembly and/or stabilization file:rat/Stxbp1/Stxbp1-deep-research-manual.md Munc18-1 domain 3a helix 12 templates VAMP2 and syntaxin, accelerating |
| GO:0035544 negative regulation of SNARE complex assembly | TAS PMID:12093152 Munc 18a binding to syntaxin 1A and 1B isoforms defines its ... | KEEP AS NON CORE | Summary: Binary Munc18-1/closed syntaxin-1 complex blocks SNARE assembly. Reason: Real inhibitory mode, but the physiological core is templating assembly. Supporting Evidence: PMID:12093152 we showed the inhibitory role of Munc-18a in the formation of syntaxin 1-synaptobrevin/VAMP complexes regardless of the isoforms PMID:18337752 When the syntaxin 1a N-peptide is bound to Munc18a, SNARE complex formation is blocked |
| GO:0042802 identical protein binding | IPI PMID:17442889 A cytosolic splice variant of Cab45 interacts with Munc18b a... | UNDECIDED | Summary: Self-association of Munc18-1 not described in the cached abstract. Reason: The abstract of PMID:17442889 describes Cab45b-Munc18 interactions; the evidence for Munc18-1 homo-interaction could not be checked. |
| GO:0043195 terminal bouton | HDA PMID:24876496 Composition of isolated synaptic boutons reveals the amounts... | ACCEPT | Summary: Detected in isolated synaptic boutons by quantitative proteomics. Reason: Consistent with presynaptic localization. Supporting Evidence: PMID:24876496 combining quantitative immunoblotting and mass spectrometry to determine protein numbers |
| GO:0043274 phospholipase binding | IDA PMID:14744865 Munc-18-1 inhibits phospholipase D activity by direct intera... | KEEP AS NON CORE | Summary: Munc18-1 binds and inhibits PLD. Reason: Direct interaction shown with purified proteins; peripheral to SNARE function. Supporting Evidence: PMID:14744865 The direct association between PLD and Munc-18-1 was confirmed by in vitro binding analysis using the purified proteins |
| GO:0043306 positive regulation of mast cell degranulation | IEA GO_REF:0000117 | MODIFY | Summary: Munc18 participates in mast-cell degranulation rather than regulating it. Reason: Knockdown eliminates degranulation and Munc18-1 re-expression rescues; the protein executes the SNARE step, so mast cell degranulation (GO:0043303). Proposed replacements: mast cell degranulation Supporting Evidence: PMID:23487749 Double knockdown of Munc18-1 and Munc18-2 in RBL-2H3 mast cells eliminates both IgE-dependent and ionomycin-induced degranulation PMID:23487749 These phenotypes were effectively rescued on reexpression of wild-type Munc18-1 or Munc18-2 but not the mutants (F115E, E132A, and F115E/E132A) in the hydrophobic pocket of Munc18 |
| GO:0043306 positive regulation of mast cell degranulation | IMP PMID:23487749 Crucial role of the hydrophobic pocket region of Munc18 prot... | MODIFY | Summary: Munc18-1 rescues degranulation in Munc18-1/2 knockdown RBL-2H3 cells. Reason: Knockdown eliminates degranulation and Munc18-1 re-expression rescues; the protein executes the SNARE step, so mast cell degranulation (GO:0043303). Proposed replacements: mast cell degranulation Supporting Evidence: PMID:23487749 Double knockdown of Munc18-1 and Munc18-2 in RBL-2H3 mast cells eliminates both IgE-dependent and ionomycin-induced degranulation PMID:23487749 These phenotypes were effectively rescued on reexpression of wild-type Munc18-1 or Munc18-2 but not the mutants (F115E, E132A, and F115E/E132A) in the hydrophobic pocket of Munc18 |
| GO:0043524 negative regulation of neuron apoptotic process | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Neurodegeneration in knockout is secondary. Reason: Neuronal death in Munc18-1 null neurons is a consequence of loss of the protein, not an anti-apoptotic activity. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Neurodegeneration in null mice is secondary. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0045335 phagocytic vesicle | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Detected on macrophage phagosomes (mouse). Reason: Peripheral, non-neuronal location. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. |
| GO:0045921 positive regulation of exocytosis | IMP PMID:20801887 Vesicle fusion probability is determined by the specific int... | MODIFY | Summary: Munc18 is required for PC12 dense-core vesicle exocytosis and raises fusion probability (full text read). Reason: Silencing abolishes stimulated exocytosis and wild-type Munc18 fully rescues; N-peptide (mode 2/3) binding raises fusion probability ~5-fold. Munc18 is an essential component of the exocytic machinery, so dense core granule exocytosis (GO:1990504) is the precise process. Proposed replacements: dense core granule exocytosis Supporting Evidence: PMID:20801887 In the absence of munc18, stimulated exocytosis was not significantly different from basal secretion PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 PMID:20801887 We conclude that the presence of munc18 molecules, engaged in regulated mode 2/3 interaction with syntaxin, exerts a strong positive effect on a specific postdocking pool of vesicles, increasing the probability of fusion by a factor of 5 |
| GO:0045956 positive regulation of calcium ion-dependent exocytosis | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Munc18-1 levels modulate Ca2+-dependent release (mouse). Reason: Consistent with its role in exocytosis; regulation framing is peripheral. Supporting Evidence: PMID:15563604 Expression of these mutants in chromaffin cells either increased the rate and extent of exocytosis or altered the kinetics of individual release events |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:15869823 Nuclear localization of Munc18-1 (p67) in the adult rat brai... | KEEP AS NON CORE | Summary: Perinuclear/nuclear Munc18-1 in PC12 and neurons. Reason: Non-canonical location of unknown function. Supporting Evidence: PMID:15869823 confirmed the nuclear localization of this protein in PC12 cells and adult rat brain neurons by immunofluorescence and immunoelectron microscopy |
| GO:0050821 protein stabilization | IDA PMID:15935055 Munc18-1 stabilizes syntaxin 1, but is not essential for syn... | KEEP AS NON CORE | Summary: Munc18-1 stabilizes syntaxin-1. Reason: Pulse-chase evidence for syntaxin-1 stabilization; secondary to the fusion role. Supporting Evidence: PMID:15935055 Pulse-chase analysis in transfected HEK293 cells revealed that Munc18-1 directly promotes the stability of syntaxin 1, consistent with a chaperone function |
| GO:0060090 molecular adaptor activity | EXP PMID:21193638 Possible roles for Munc18-1 domain 3a and Syntaxin1 N-peptid... | MODIFY | Summary: Munc18-1 binds syntaxin-1 and VAMP2 and templates their assembly. Reason: Molecular adaptor activity is right in essence but general; protein-macromolecule adaptor activity (GO:0030674) describes the template that brings syntaxin-1 and VAMP2 together. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:21193638 We also find that Syntaxin1, with an N peptide and a physically anchored C terminus, binds to Munc18-1 and that this complex can participate in SNARE complex formation PMID:24532794 the data suggest that helix 12 provides a folding template for VAMP2, accelerating SNAREpin assembly and membrane fusion |
| GO:0060292 long-term synaptic depression | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: LTD changes in mutant mice are indirect. Reason: A plasticity phenotype downstream of altered release, not a process Munc18-1 executes. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Plasticity phenotype downstream of release. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0061588 calcium activated phospholipid scrambling | IGI PMID:22810233 SNAREpin assembly by Munc18-1 requires previous vesicle dock... | MARK AS OVER ANNOTATED | Summary: Calcium-activated phospholipid scrambling is unrelated to the cited reconstitution study. Reason: PMID:22810233 reconstitutes Syt1/SNARE/Munc18-1 vesicle docking and fusion; no lipid scrambling is described. The term (a TMEM16-type process) appears mis-selected, probably for a Ca2+-triggered fusion term. Abstract only, so marked rather than removed. Supporting Evidence: PMID:22810233 vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion |
| GO:0061670 evoked neurotransmitter secretion | IMP PMID:19255244 Munc18-1 binding to the neuronal SNARE complex controls syna... | ACCEPT | Summary: Munc18-1 is required for evoked release (full text read). Reason: Rescue of evoked release in KO neurons by wild-type Munc18-1. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles |
| GO:0070527 platelet aggregation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Platelet aggregation from peptide inhibition dominated by Munc18c. Reason: The human source (PMID:12773094) used Munc18a/Munc18c-derived peptides in permeabilized platelets; the authors conclude Munc18c has the dominant role. A role for Munc18-1 specifically in platelet degranulation is not established. Supporting Evidence: PMID:12773094 suggest a dominant role for Munc18c in all three granule-release events |
| GO:0070527 platelet aggregation | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: Platelet aggregation from peptide inhibition dominated by Munc18c. Reason: The human source (PMID:12773094) used Munc18a/Munc18c-derived peptides in permeabilized platelets; the authors conclude Munc18c has the dominant role. A role for Munc18-1 specifically in platelet degranulation is not established. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK WRONG ORTHOLOG OR PARALOG Sources checked: UniProtKB:P61764 SOURCE WEAK OR INFERRED Human peptide-inhibition study; Munc18c dominant. Supporting Evidence: PMID:12773094 suggest a dominant role for Munc18c in all three granule-release events |
| GO:0071346 cellular response to type II interferon | ISO GO_REF:0000121 | MARK AS OVER ANNOTATED | Summary: IFN-gamma response in macrophages is not a Munc18-1 process. Reason: Donor is a mouse macrophage phagosome localization study; response to interferon is context, not function. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:107363 SOURCE WEAK OR INFERRED Macrophage localization study, not a response process. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. |
| GO:0072659 protein localization to plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Munc18-1 supports membrane delivery of syntaxin-1. Reason: Chaperoning syntaxin-1 to the plasma membrane is real but secondary. Supporting Evidence: PMID:17543282 Munc18-1 is found not to be essential for Stx1A cluster distribution, despite important role in stabilizing membrane delivery of Stx1A PMID:26359495 with syntaxin 1 in the absence of Munc18a, when syntaxin 1 is retained in the ER |
| GO:0072659 protein localization to plasma membrane | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Munc18-1 supports membrane delivery of syntaxin-1. Reason: Chaperoning syntaxin-1 to the plasma membrane is real but secondary. Supporting Evidence: PMID:17543282 Munc18-1 is found not to be essential for Stx1A cluster distribution, despite important role in stabilizing membrane delivery of Stx1A PMID:26359495 with syntaxin 1 in the absence of Munc18a, when syntaxin 1 is retained in the ER |
| GO:0098688 parallel fiber to Purkinje cell synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Active at cerebellar parallel fibre synapses. Reason: Synapse-type specific location; peripheral. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0098793 presynapse | IDA PMID:15869823 Nuclear localization of Munc18-1 (p67) in the adult rat brai... | ACCEPT | Summary: Presynaptic localization. Reason: Munc18-1 acts at presynaptic terminals. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes PMID:24876496 combining quantitative immunoblotting and mass spectrometry to determine protein numbers |
| GO:0098794 postsynapse | IDA PMID:15869823 Nuclear localization of Munc18-1 (p67) in the adult rat brai... | KEEP AS NON CORE | Summary: Postsynaptic labelling in immuno-EM (curated IDA). Reason: Cannot verify (abstract only); Munc18-1 function is presynaptic, so non-core. Supporting Evidence: PMID:15869823 confirmed the nuclear localization of this protein in PC12 cells and adult rat brain neurons by immunofluorescence and immunoelectron microscopy |
| GO:0098831 presynaptic active zone cytoplasmic component | ISO GO_REF:0000121 | ACCEPT | Summary: Presynaptic active zone cytoplasmic component. Reason: Where priming and fusion occur. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Involved in the release of neurotransmitters from neurons through interacting with SNARE complex component STX1A and mediating the assembly of the SNARE complex at synaptic membranes |
| GO:0098888 extrinsic component of presynaptic membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Peripheral (extrinsic) association with presynaptic membrane. Reason: Matches peripheral membrane topology via syntaxin-1. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0098888 extrinsic component of presynaptic membrane | ISO GO_REF:0000121 | ACCEPT | Summary: Peripheral (extrinsic) association with presynaptic membrane. Reason: Matches peripheral membrane topology via syntaxin-1. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. PMID:12093152 revealed syntaxin 1-dependent localization of Munc-18a in the plasma membrane |
| GO:0098978 glutamatergic synapse | ISO GO_REF:0000121 | KEEP AS NON CORE | Summary: Acts at glutamatergic synapses. Reason: Correct but synapse-type specific; Munc18-1 is required at all fast synapses. Supporting Evidence: PMID:19255244 we show that lentiviral expression of Munc18-1 rescues abrogation of release in Munc18-1 knockout mice |
| GO:0099023 vesicle tethering complex | IDA PMID:22810233 SNAREpin assembly by Munc18-1 requires previous vesicle dock... | MARK AS OVER ANNOTATED | Summary: Munc18-1 is not a vesicle tethering complex subunit. Reason: The cited study states that synaptotagmin-1 docks vesicles and Munc18-1 acts afterwards to accelerate SNAREpin assembly. Abstract only, so marked rather than removed. Supporting Evidence: PMID:22810233 vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion |
| GO:0099502 calcium-dependent activation of synaptic vesicle fusion | IGI PMID:22810233 SNAREpin assembly by Munc18-1 requires previous vesicle dock... | MARK AS OVER ANNOTATED | Summary: Munc18-1 is not the Ca2+-triggering step. Reason: Munc18-1 accelerates SNARE assembly before Ca2+ triggering; binding mutants impair priming but not Ca2+-triggered fusion of primed vesicles. Supporting Evidence: PMID:22810233 vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion PMID:19255244 Lentiviral rescue experiments reveal that such disruption selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed vesicles |
| GO:0099523 presynaptic cytosol | ISO GO_REF:0000121 | ACCEPT | Summary: Presynaptic cytosol. Reason: Soluble presynaptic pool. Supporting Evidence: file:rat/Stxbp1/Stxbp1-uniprot.txt Membrane; Peripheral membrane protein. |
| GO:0099525 presynaptic dense core vesicle exocytosis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Neuronal dense-core vesicle exocytosis inherited from unc-18 clade. Reason: Plausible and consistent with neuroendocrine data; secondary to synaptic vesicle release. Supporting Evidence: PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 |
| GO:0160321 vesicle docking activity | ISO GO_REF:0000121 | ACCEPT | Summary: Munc18-1 is required for dense-core vesicle docking (mouse chromaffin). Reason: Mouse knockout chromaffin cells lose docked vesicles; Munc18-1 with syntaxin-1/SNAP-25 forms the acceptor that attaches vesicles. Supporting Evidence: PMID:21193638 Munc18-1 participates in synaptic vesicle fusion via dual roles: as a docking/chaperone protein by binding closed Syntaxin1, and as a fusion protein that binds SNARE complexes in a Syntaxin1 N-peptide dependent manner PMID:9395480 In brain, Mint proteins are part of a multimeric complex containing Munc18-1 and syntaxin that likely functions as an intermediate in synaptic vesicle docking/fusion |
| GO:0160321 vesicle docking activity | ISS GO_REF:0000024 | ACCEPT | Summary: Munc18-1 is required for dense-core vesicle docking (mouse chromaffin). Reason: Mouse knockout chromaffin cells lose docked vesicles; Munc18-1 with syntaxin-1/SNAP-25 forms the acceptor that attaches vesicles. Supporting Evidence: PMID:21193638 Munc18-1 participates in synaptic vesicle fusion via dual roles: as a docking/chaperone protein by binding closed Syntaxin1, and as a fusion protein that binds SNARE complexes in a Syntaxin1 N-peptide dependent manner PMID:9395480 In brain, Mint proteins are part of a multimeric complex containing Munc18-1 and syntaxin that likely functions as an intermediate in synaptic vesicle docking/fusion |
| GO:1903296 positive regulation of glutamate secretion, neurotransmission | IMP PMID:16951547 Munc18 plays an important role in the regulation of glutamat... | MODIFY | Summary: Antisense knockdown reduces hypothalamic glutamate release. Reason: Munc18-1 executes release; glutamate secretion, neurotransmission (GO:0061535) is the process, not its regulation. Proposed replacements: glutamate secretion, neurotransmission Supporting Evidence: PMID:16951547 Intracerebroventricular administration of an antisense oligodeoxynucleotide against munc18-1 mRNA significantly decreased glutamate release and delayed the day of puberty onset |
| GO:1990504 dense core granule exocytosis | ISO GO_REF:0000121 | ACCEPT | Summary: Dense core granule exocytosis (mouse chromaffin, rat PC12). Reason: Core in neuroendocrine cells. Supporting Evidence: PMID:20801887 In the absence of munc18, stimulated exocytosis was not significantly different from basal secretion PMID:20801887 Exocytosis in silenced PC-12 cells was fully rescued (to levels observed in native PC12 cells) by introducing a fluorescent fusion of wild type munc18 |
| GO:2000367 regulation of acrosomal vesicle exocytosis | IEA GO_REF:0000107 | MODIFY | Summary: Munc18-1 is essential for acrosomal exocytosis (human sperm). Reason: Antibody inactivation blocks the trans-SNARE step; Munc18-1 participates, so acrosomal vesicle exocytosis (GO:0060478). Proposed replacements: acrosomal vesicle exocytosis Supporting Evidence: PMID:23091057 we describe the presence of Munc18-1 in human sperm and show that this protein has an essential role in acrosomal exocytosis PMID:23091057 our results indicate that Munc18-1 plays a key role in the dynamics of trans-SNARE complex assembly and/or stabilization |
| GO:2000367 regulation of acrosomal vesicle exocytosis | ISO GO_REF:0000121 | MODIFY | Summary: Munc18-1 is essential for acrosomal exocytosis (human sperm). Reason: Antibody inactivation blocks the trans-SNARE step; Munc18-1 participates, so acrosomal vesicle exocytosis (GO:0060478). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P61764 SUPPORTS TRANSFER Human sperm study shows participation in acrosomal exocytosis, not regulation. Proposed replacements: acrosomal vesicle exocytosis Supporting Evidence: PMID:23091057 we describe the presence of Munc18-1 in human sperm and show that this protein has an essential role in acrosomal exocytosis PMID:23091057 our results indicate that Munc18-1 plays a key role in the dynamics of trans-SNARE complex assembly and/or stabilization |
| GO:7770062 vesicle membrane tethering activity | IDA PMID:22810233 SNAREpin assembly by Munc18-1 requires previous vesicle dock... | MARK AS OVER ANNOTATED | Summary: Vesicle membrane tethering is performed by synaptotagmin-1 in the cited assay. Reason: The cited study states that synaptotagmin-1 docks vesicles and Munc18-1 acts afterwards to accelerate SNAREpin assembly. Abstract only, so marked rather than removed. Supporting Evidence: PMID:22810233 vesicle docking by synaptotagmin 1 is a prerequisite for Munc18-1 to accelerate trans-SNARE complex (SNAREpin) assembly and membrane fusion |
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Download this section (compressed HTML)Q: Should the Munc18-1 template role in SNARE assembly have a dedicated MF term (SNARE complex assembly template/chaperone activity) rather than protein-macromolecule adaptor activity?
Q: Were the RGD rows from PMID:22810233 (vesicle membrane tethering activity, vesicle tethering complex, calcium activated phospholipid scrambling) intended for SNARE complex assembly or synaptic vesicle fusion?
Q: Does Munc18-1 contribute to platelet granule secretion independently of Munc18b/Munc18c?
Experiment: Platelet-specific Stxbp1 deletion in mice, with and without Stxbp3 deletion, to test whether Munc18-1 contributes to platelet granule exocytosis.
Experiment: Single-vesicle TIRF fusion assays in Munc18-1-silenced PC12 cells rescued with the L348R helix-12 mutant, to test whether the VAMP2 template function is required for the high fusion-probability vesicle pool.
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