Affinage

STXBP5

Syntaxin-binding protein 5 · UniProt Q5T5C0

Length
1151 aa
Mass
127.6 kDa
Annotated
2026-04-28
71 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STXBP5 (tomosyn-1) is a soluble R-SNARE protein that functions as a master negative regulator of SNARE-dependent exocytosis across diverse secretory cell types, including neurons, neuroendocrine cells, pancreatic beta cells, endothelial cells, platelets, and mast cells. It inhibits vesicle fusion through two mechanistically distinct domains: a C-terminal VAMP-like domain that forms a non-fusogenic four-helical SNARE bundle with syntaxin and SNAP-25, competitively excluding synaptobrevin from productive SNARE complexes (PMID:12782620, PMID:15316007), and an N-terminal WD40 β-propeller domain that oligomerizes SNARE complexes and is independently required for inhibition of vesicle priming (PMID:18936251, PMID:17666050). Its inhibitory activity is dynamically regulated by PKA phosphorylation (relieving syntaxin binding to promote neurotransmitter release), Akt phosphorylation at Ser-783 (derepressing GLUT4 exocytosis), SUMOylation at K298/K730 (required for syntaxin sequestration in beta cells), and HRD1-mediated ubiquitin-proteasomal degradation (PMID:16186257, PMID:25725259, PMID:28325894, PMID:29269412). In the vasculature, STXBP5 interacts with syntaxin-4 to inhibit endothelial Weibel-Palade body exocytosis of von Willebrand factor while promoting platelet granule secretion, and a human GWAS variant (N436S) has been functionally validated to lower plasma vWF and thrombosis in CRISPR knock-in mice (PMID:25244095, PMID:28062498).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    The discovery of tomosyn as a syntaxin-1-binding protein that displaces Munc18 and inhibits Ca²⁺-dependent exocytosis established the founding principle that a soluble factor can negatively regulate SNARE-mediated fusion.

    Evidence Co-immunoprecipitation, biochemical fractionation, and PC12 overexpression exocytosis assay

    PMID:9620695

    Open questions at the time
    • Mechanism of inhibition (SNARE competition vs. other) not yet defined
    • No structural information on the tomosyn-syntaxin interaction
    • In vivo relevance not demonstrated
  2. 2003 High

    Demonstration that the C-terminal VAMP-like domain forms a stable four-helical SNARE bundle with syntaxin-1/SNAP-25 — competing directly with synaptobrevin — resolved the molecular mechanism of tomosyn's inhibitory activity and extended its scope to non-neuronal t-SNAREs (syntaxin-4/SNAP-23).

    Evidence In vitro reconstitution with recombinant proteins, CD spectroscopy, competition assays; parallel yeast two-hybrid and GLUT4 translocation assays in adipocytes

    PMID:12782620 PMID:12832401

    Open questions at the time
    • Role of the large N-terminal WD40 domain unknown
    • No atomic-resolution structure yet
  3. 2004 High

    The crystal structure of the tomosyn SNARE complex at 2.0 Å, together with electrophysiological evidence that tomosyn inhibits the vesicle priming step without affecting docking, defined tomosyn as a decoy R-SNARE that traps syntaxin in a non-productive complex at the priming stage.

    Evidence X-ray crystallography and CD spectroscopy; capacitance measurements and amperometry in chromaffin cells

    PMID:14983051 PMID:15316007

    Open questions at the time
    • Priming inhibition could involve additional WD40-dependent mechanisms
    • Regulation of tomosyn activity not addressed
  4. 2005 High

    Identification of PKA-mediated phosphorylation of tomosyn — which reduces syntaxin binding and enhances neurotransmitter release — and ROCK-mediated phosphorylation of syntaxin-1 — which increases tomosyn affinity — revealed that opposing kinase pathways bidirectionally tune tomosyn's inhibitory function.

    Evidence In vitro kinase assays, co-immunoprecipitation, electrophysiology in SCG neurons; ROCK kinase assays and growth cone imaging

    PMID:15240567 PMID:16186257

    Open questions at the time
    • Specific phosphorylation sites on tomosyn for PKA not fully mapped
    • In vivo significance of ROCK-tomosyn axis in neurons not established
  5. 2006 High

    Genetic loss of the C. elegans ortholog tom-1 confirmed the conserved role of tomosyn as a negative regulator of vesicle priming in vivo, and epistasis with unc-13 placed tomosyn functionally downstream of the priming machinery.

    Evidence Electrophysiology, electron microscopy, and genetic epistasis in C. elegans

    PMID:16895441

    Open questions at the time
    • Mammalian genetic loss-of-function not yet available
    • Whether the WD40 or SNARE domain mediates in vivo priming inhibition unclear
  6. 2007 Medium

    Structure–function dissection in chromaffin cells unexpectedly showed that the N-terminal WD40 domain, not the C-terminal SNARE domain, is the primary determinant of vesicle priming inhibition, challenging the SNARE-competition-only model.

    Evidence Domain deletion mutant overexpression with capacitance measurements in chromaffin cells

    PMID:17666050

    Open questions at the time
    • Mechanism by which WD40 domain inhibits priming not identified
    • Apparent contradiction with SNARE-domain-centric model not resolved
  7. 2008 High

    The discovery that the WD40 domain catalyzes oligomerization of SNARE complexes provided a second, distinct inhibitory mechanism and reconciled the WD40-dependent priming inhibition with the SNARE-domain competition model as dual, complementary pathways.

    Evidence Microinjection into neurons, biochemical analysis of SNARE complex oligomerization, tomosyn-deficient mouse neurons

    PMID:18936251

    Open questions at the time
    • Structural basis of WD40-mediated SNARE oligomerization unknown
    • Relative contributions of the two mechanisms in different cell types not quantified
  8. 2014 High

    A convergence of studies in 2014 established STXBP5's vascular function — inhibiting endothelial Weibel-Palade body exocytosis of vWF via syntaxin-4 while promoting platelet granule secretion via syntaxin-11/SNAP-23 — and demonstrated that the NTD recruits tomosyn to fusion sites while the CTD blocks v-SNARE pairing in reconstituted fusion.

    Evidence Stxbp5 KO mouse with thrombosis/bleeding phenotypes, siRNA in endothelial cells, co-IP with syntaxin-4 and syntaxin-11, reconstituted liposome fusion with purified full-length protein

    PMID:25063806 PMID:25244094 PMID:25244095

    Open questions at the time
    • Why tomosyn promotes platelet secretion but inhibits endothelial secretion mechanistically unclear
    • Role of specific platelet SNARE isoforms not fully dissected
  9. 2014 Medium

    Identification of SUMOylation (by PIASγ, SUMO-2/3 at K730) and phosphorylation-dependent ubiquitin-proteasomal degradation (by Hrd-1 E3 ligase) of tomosyn established post-translational control of tomosyn protein levels and activity as a regulatory layer for insulin secretion.

    Evidence SUMO modification assays, yeast two-hybrid with PIASγ, mass spectrometry-mapped phosphosites, ubiquitination assays with Hrd-1

    PMID:24614299 PMID:25002582

    Open questions at the time
    • In vivo significance of SUMOylation for insulin secretion not demonstrated in animal models
    • Whether Hrd-1 regulation applies to tomosyn-1 (not just tomosyn-2) was not shown at this point
  10. 2015 Medium

    Akt phosphorylation at Ser-783 was shown to relieve tomosyn's inhibition of syntaxin-4 interaction, linking insulin/PI3K signaling directly to derepression of GLUT4 exocytosis, while tomosyn knockdown at hippocampal mossy fiber synapses revealed a role in synaptic facilitation and LTP.

    Evidence In vitro kinase assay with Akt, GLUT4 surface assay; shRNA/optogenetic approach with slice electrophysiology

    PMID:25725259 PMID:26166572

    Open questions at the time
    • In vivo validation of Akt-tomosyn axis in adipose tissue lacking
    • Mechanism by which tomosyn loss impairs facilitation (expected to enhance release) not fully explained
  11. 2017 Medium

    Multiple regulatory layers were defined: glucose-dependent de-SUMOylation at K298 releases syntaxin-1A in beta cells; secretagogin dissociates from tomosyn upon Ca²⁺ to promote exocytosis; HRD1 ubiquitinates tomosyn-1 to control dendritic spine density; and the human GWAS variant N436S was validated by CRISPR knock-in to reduce vWF and thrombosis.

    Evidence SUMO mutagenesis and insulin secretion in human beta cells; HRD1 in vitro ubiquitination and spine analysis in neurons; CRISPR/Cas9 knock-in mouse for N436S

    PMID:28062498 PMID:28325894 PMID:29269412

    Open questions at the time
    • Structural basis for how N436S alters tomosyn function unknown
    • Role of secretagogin-tomosyn axis beyond beta cells not explored
    • Spine density effect appears SNARE-domain-independent — mechanism unclear
  12. 2018 Medium

    Reconstitution of the full SNARE assembly pathway showed that NSF/α-SNAP disassembles the tomosyn-syntaxin arrest, enabling Munc18-1 binding, after which Munc13-1 selectively channels syntaxin toward synaptobrevin rather than tomosyn — placing tomosyn within the ordered priming cascade.

    Evidence In vitro reconstitution with purified NSF, α-SNAP, Munc18-1, Munc13-1, and tomosyn

    PMID:29485200

    Open questions at the time
    • Order of events not validated in intact synapses
    • Whether Munc13-1 selectivity applies to all tomosyn isoforms untested
  13. 2020 High

    CRISPR double KO of both tomosyn genes in adipocytes confirmed their non-redundant inhibition of all SNARE complexes underlying GLUT4 exocytosis, while neuronal studies revealed a SNARE-independent function: tomosyn's WD40 domain inhibits RhoA GTPase to maintain dendritic arborization and AMPA receptor surface expression, with ASD-associated WD40 variants showing loss of this function.

    Evidence CRISPR-Cas9 DKO adipocytes with reconstituted liposome fusion; shRNA in primary neurons with RhoA activity assay, surface AMPAR staining, and ASD variant rescue

    PMID:32133675 PMID:32851733

    Open questions at the time
    • Mechanism by which WD40 domain inhibits RhoA (direct or indirect) not defined
    • ASD variant effects not validated in animal behavior
  14. 2023 Medium

    Conditional double KO of Stxbp5/Stxbp5l in mouse neurons unexpectedly revealed that tomosyns regulate dense-core vesicle biogenesis at the trans-Golgi network — decreasing DCV cargo levels without affecting fusion — a function independent of the SNARE domain, expanding tomosyn's role beyond fusion inhibition.

    Evidence Conditional DKO mouse, pHluorin single-vesicle DCV assay, electron microscopy, live TGN imaging

    PMID:37695731

    Open questions at the time
    • Molecular mechanism of TGN cargo sorting regulation unknown
    • Which WD40-interacting partners at the TGN mediate this effect not identified
    • Relevance to synaptic vesicle cargo not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the structural basis for WD40-mediated SNARE oligomerization and RhoA inhibition; how tomosyn simultaneously promotes platelet secretion while inhibiting endothelial exocytosis; the mechanism underlying tomosyn's role in DCV biogenesis at the TGN; and whether ASD-associated WD40 variants cause behavioral phenotypes in vivo.
  • No structure of full-length tomosyn or WD40 domain in complex with SNARE oligomers
  • Cell-type-specific functions (promote vs. inhibit secretion) mechanistically unexplained
  • DCV biogenesis pathway partners unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0005198 structural molecule activity 3 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005794 Golgi apparatus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-109582 Hemostasis 3
Partners
HRD1SCGNSNAP23SNAP25STX11STX1ASTX4SYNGR1
Complex memberships
tomosyn-syntaxin-1-SNAP-25 ternary SNARE complextomosyn-syntaxin-4-SNAP-23 ternary SNARE complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Tomosyn (STXBP5) binds syntaxin-1, dissociates Munc18 from syntaxin-1, and forms a novel 10S complex with syntaxin-1, SNAP-25, and synaptotagmin; high-level expression reduces Ca2+-dependent exocytosis in PC12 cells Co-immunoprecipitation, biochemical fractionation, PC12 cell overexpression assay Neuron High 9620695
2003 The C-terminal R-SNARE motif of tomosyn forms a stable four-helical SNARE core complex with syntaxin-1 and SNAP-25, competing with synaptobrevin for SNARE complex formation and inhibiting exocytosis; complexes are disassembled by NSF/α-SNAP In vitro reconstitution with recombinant proteins, CD spectroscopy, inside-out plasma membrane sheets competition assay, PC12 cell exocytosis assay The Journal of biological chemistry High 12782620
2004 Crystal structure of the tomosyn SNARE core complex at 2.0-Å resolution reveals a four-helical bundle nearly identical to the synaptobrevin SNARE complex; synaptobrevin cannot displace the tomosyn helix and vice versa, indicating both represent stable end products X-ray crystallography, CD spectroscopy The Journal of biological chemistry High 15316007
2004 Tomosyn inhibits the priming step of large dense-core vesicle exocytosis in chromaffin cells in a calcium-dependent manner, reducing fusion-competent vesicle number without affecting docked vesicle number or single-vesicle fusion kinetics Morphological analysis, capacitance measurements, amperometry, chromaffin cell overexpression Proceedings of the National Academy of Sciences of the United States of America High 14983051
2004 ROCK (activated by Rho GTPase) phosphorylates syntaxin-1, increasing its affinity for tomosyn and forming a stable tomosyn-syntaxin complex that inhibits SNARE complex formation; this localizes tomosyn to growth cone palms to regulate neurite extension and retraction Biochemical interaction assays, kinase assays, confocal microscopy of growth cones The Journal of cell biology Medium 15240567
2005 PKA directly phosphorylates tomosyn, reducing its interaction with syntaxin-1 and enhancing SNARE complex formation; this increases the readily releasable pool and neurotransmitter release in SCG neurons, mediating PACAP-induced synaptic facilitation In vitro kinase assay, co-immunoprecipitation, electrophysiology in cultured SCG neurons The Journal of cell biology High 16186257
2006 C. elegans TOM-1 (tomosyn ortholog) negatively regulates synaptic vesicle priming at the NMJ; tom-1 mutants show increased plasma membrane-contacting vesicles and enhanced hyperosmotic responses; tom-1 unc-13 double mutants partially suppress unc-13 priming defects Electrophysiology, electron microscopy ultrastructure, hyperosmotic response assay, genetic epistasis PLoS biology High 16895441
2006 Tomosyn-1 is expressed in pancreatic beta-cells, co-immunoprecipitates with syntaxin-1, and negatively regulates insulin exocytosis; siRNA knockdown increases exocytosis while overexpression decreases it Co-immunoprecipitation, siRNA knockdown, overexpression, exocytosis measurement Diabetes Medium 16505218
2006 Tomosyn-1 in pancreatic beta-cells is involved in a post-docking event required for exocytosis; silencing tomosyn-1 does not affect docked granule number but reduces stimulus-induced exocytosis; the SNARE-like domain forms a complex with syntaxin-1 and SNAP-25 with weaker binding forces than VAMP2 Atomic force microscopy, RNA interference, electron microscopy, exocytosis assay Journal of cell science Medium 16787939
2003 Tomosyn interacts with t-SNAREs syntaxin-4 and SNAP-23 through its VAMP-2-like domain, forming a ternary complex competitively inhibited by VAMP-2; overexpression in adipocytes inhibits insulin-stimulated GLUT4 translocation to the plasma membrane Yeast two-hybrid, in vitro binding, GLUT4-GFP translocation assay in 3T3-L1 adipocytes The Journal of biological chemistry Medium 12832401
2008 Tomosyn inhibits SNARE complex formation and neurotransmitter release through dual mechanisms: (1) C-terminal VAMP-like domain sequesters syntaxin-1; (2) N-terminal WD-40 repeat domain catalyzes oligomerization of SNARE complexes; microinjection of the WD-40 domain into neurons prevented stimulated acetylcholine release Microinjection, biochemical analysis of SNARE complex oligomerization, tomosyn-deficient mouse neurons The Journal of cell biology High 18936251
2007 Tomosyn WD-40 domain integrity (not the SNARE domain) is required for inhibition of vesicle priming; a truncation lacking the entire SNARE domain still inhibits exocytosis, while N-terminal truncations abolish inhibition despite retaining syntaxin binding Domain deletion mutant overexpression in chromaffin cells, capacitance measurements Journal of neurochemistry Medium 17666050
2007 Secretagogue stimulation causes rapid translocation of tomosyn from cytosol to plasma membrane and increases tomosyn-syntaxin-1A interaction; this is mediated by RhoA/ROCK signaling, as ROCK inhibition blocks the secretagogue-induced tomosyn-syntaxin interaction Live-cell imaging, FRAP, co-immunoprecipitation, pharmacological inhibition in chromaffin cells The Journal of biological chemistry Medium 17545156
2011 m-tomosyn-1 is a substrate for SUMO-2/3 conjugation; mutation of the SUMO target site (Lys-730) enhances tomosyn-1 inhibition of secretion without altering interaction with syntaxin-1A; loop domains 1 and 3 of the β-propeller core are required for inhibitory activity independent of SNARE pairing Site-directed mutagenesis, SUMO conjugation assay, secretion assay in PC12 cells, homology modeling The Journal of biological chemistry Medium 21330375
2014 STXBP5 is expressed in human endothelial cells, colocalizes and interacts with syntaxin-4; STXBP5 knockdown increases vWF and P-selectin exocytosis; Stxbp5 KO mice have elevated plasma vWF, increased platelet-endothelial interactions, but also impaired platelet secretion and hemostasis Co-immunoprecipitation, siRNA knockdown, Stxbp5 KO mouse model, tail bleeding, thrombosis assay The Journal of clinical investigation High 25244095
2014 STXBP5 (tomosyn-1) in platelets interacts with syntaxin-11/SNAP-23 heterodimers and the platelet cytoskeleton; Stxbp5 KO mice show defective secretion from all three granule types and altered granule cargo levels, demonstrating a role in platelet granule cargo packaging and secretion Mass spectrometry identification, co-immunoprecipitation, fractionation, Stxbp5 KO mouse, lumi-aggregometry, FACS The Journal of clinical investigation High 25244094
2014 The C-terminal domain (CTD) of tomosyn mediates inhibition of SNARE-dependent membrane fusion by recognizing the t-SNARE complex and preventing v-SNARE pairing; the N-terminal domain (NTD) is required for binding to syntaxin monomer and recruitment to fusion sites; tomosyn inhibition is dominant over Munc18 stimulatory activity In vitro reconstituted liposome fusion assay, purified full-length and truncated proteins, binding assays The Journal of biological chemistry High 25063806
2014 Tomosyn-2 is phosphorylated in response to high glucose, phorbol esters, and cAMP analogs; phosphomimetic mutants show enhanced proteasomal degradation and reduced inhibition of insulin secretion; Hrd-1 E3 ubiquitin ligase binds tomosyn-2 and promotes its ubiquitination and degradation 32P labeling, mass spectrometry, site-directed mutagenesis, proteomic screen, ubiquitination assay, shRNA knockdown The Journal of biological chemistry High 25002582
2014 Tomosyn is organized in small clusters adjacent to syntaxin clusters on the plasma membrane; tomosyn inhibition of exocytosis is mediated through tomosyn-syntaxin-SNAP25 ternary complexes rather than tomosyn-syntaxin binary complexes; WD-40 core residues 537-578 and 897-917 are required for SNAP25 binding dSTORM super-resolution microscopy, deletion mutant analysis, FRAP The Journal of biological chemistry Medium 24782308
2014 Silencing STXBP5 in vascular endothelial cells decreases tPA release, implicating STXBP5 in tPA exocytosis regulation siRNA knockdown, tPA release assay in endothelial cells Arteriosclerosis, thrombosis, and vascular biology Medium 24578379
2015 Tomosyn knockdown at hippocampal mossy fiber-CA3 synapses impairs synaptic facilitation, PKA-induced potentiation, and LTP, indicating tomosyn is a key regulator of MF-CA3 synaptic plasticity and release probability Combined shRNA knockdown and optogenetic activation, electrophysiology in hippocampal slices Cell reports Medium 26166572
2015 Tomosyn is phosphorylated by Akt at Ser-783; this phosphorylation inhibits tomosyn's interaction with syntaxin-4 and is required for insulin-stimulated GLUT4 surface expression In vitro kinase assay with Akt1/2, in vitro pull-down, intact cell phosphorylation with PI3K inhibitor, GLUT4 surface assay The international journal of biochemistry & cell biology Medium 25725259
2016 Tomo1 regulates synaptic vesicle pool partitioning (RRP, TRP, resting pool) in hippocampal neurons in an activity-dependent manner via Cdk5 phosphorylation; Tomo1 interacts with Rab3A-GTP and synapsin 1a/b VGlut1-pHluorin fluorescence imaging, co-immunoprecipitation, KD and rescue in cultured neurons The Journal of neuroscience Medium 27807164
2016 Human SNP rs1039084 (N436S) in STXBP5, introduced by CRISPR/Cas9, causes lower plasma vWF levels, decreased thrombosis, and decreased platelet secretion in mice, establishing this variant as functionally causal CRISPR/Cas9 knock-in mouse model, vWF measurement, thrombosis assay, platelet activation Arteriosclerosis, thrombosis, and vascular biology Medium 28062498
2017 SUMOylation of tomosyn-1 at K298 is required for its inhibition of insulin exocytosis by binding syntaxin-1A; glucose-dependent de-SUMOylation of tomosyn releases syntaxin-1A; Ca2+-binding protein secretagogin interacts with tomosyn-1 and dissociates in response to Ca2+ to promote exocytosis Co-immunoprecipitation, site-directed mutagenesis, SUMO modification assay, insulin secretion assay in human beta cells Scientific reports Medium 28325894
2017 Tomosyn-1 is ubiquitinated and degraded by the proteasome via an interaction with the E3 ubiquitin ligase HRD1; HRD1 knockdown increases tomosyn-1 levels and dendritic spine density; overexpression of tomosyn-1 increases spine density independently of its C-terminal R-SNARE domain Immunoprecipitation of ubiquitinated Tomo-1, in vitro ubiquitination assay, HRD1 knockdown, spine density analysis in hippocampal neurons The Journal of biological chemistry Medium 29269412
2017 C. elegans UNC-18(P334A) gain-of-function and tom-1 null mutations synergistically suppress unc-13 mutant phenotypes; biochemically, Munc18-1(P335A) shows enhanced SNARE complex formation and partially bypasses Munc13-1 requirement, demonstrating that UNC-18 and Tomosyn act antagonistically downstream of UNC-13 Genetic epistasis in C. elegans, liposome fusion assay, biochemical SNARE complex formation assay The Journal of neuroscience High 28821673
2018 Tomosyn guides SNARE complex formation: NSF/α-SNAP releases syntaxin-1 from tomosyn arrest, enabling Munc18-1/syntaxin-1 complex formation; Munc13-1 then catalyzes transit of syntaxin-1 to the SNARE complex specifically with synaptobrevin-2 but not with tomosyn In vitro reconstitution of SNARE complex assembly, pull-down assays with purified proteins FEBS letters Medium 29485200
2018 Tomosyn-1 (STXBP5) inhibits IgE/FcεRI-stimulated mast cell degranulation; after activation, tomosyn-1 is phosphorylated on serine/threonine residues by PKCδ, dissociates from syntaxin-4, and associates with syntaxin-3; high IgE increases tomosyn-1 abundance as a counterregulatory mechanism FcεRI stimulation assay, co-immunoprecipitation, phosphorylation analysis, PKCδ inhibition Science signaling Medium 29970602
2020 Tomosyn inhibits basal and insulin-stimulated GLUT4 exocytosis in adipocytes; CRISPR-Cas9 double knockout of both tomosyn-encoding genes markedly elevates GLUT4 exocytosis; in reconstituted liposome fusion, tomosyn inhibits all SNARE complexes underlying GLUT4 exocytosis, and this inhibition is relieved by NSF/α-SNAP CRISPR-Cas9 double KO in adipocytes, reconstituted liposome fusion assay, GLUT4 surface assay Traffic High 32851733
2020 Tomosyn knockdown in neurons increases RhoA GTPase activity, causing impaired dendritic arborization, spine loss, decreased surface AMPA receptor expression, and reduced mEPSC frequency; the N-terminal WD40 domain mediates RhoA inhibition; ASD-associated variants in the WD40 domain show loss-of-function for RhoA regulation shRNA knockdown in mouse primary neurons, RhoA activity assay, surface AMPA receptor staining, electrophysiology, domain mutant rescue Journal of neuroscience research Medium 32133675
2014 Tomosyn-1 interacts with the SUMO E3 ligase PIASγ through tomosyn's C-terminus and PIASγ's N-terminus; tomosyn-1 is preferentially modified by SUMO-2/3 isoform Yeast two-hybrid, reciprocal co-immunoprecipitation in HEK293T cells, SUMO modification assay PloS one Medium 24614299
2021 In Drosophila, Tomosyn acts as a decoy SNARE that reduces SNARE complex formation to set tonic (low probability) vs phasic (high probability) release properties in distinct motoneuron subclasses; loss of Tomosyn disrupts presynaptic homeostatic potentiation at tonic synapses Drosophila genetic KO, electrophysiology comparing Ib vs Is motoneurons, homeostatic plasticity assay eLife Medium 34713802
2023 Loss of tomosyns (Stxbp5 and Stxbp5l) in mouse neurons does not affect DCV fusion events but reduces intracellular DCV cargo levels (NPY, BDNF); rescue requires tomosyn but not its SNARE domain; tomosyns influence DCV biogenesis at the trans-Golgi network, decreasing TGN size and increasing DCV cargo flux speed Conditional double KO mouse, pHluorin-based single-vesicle DCV exocytosis assay, electron microscopy, live imaging of TGN eLife Medium 37695731
2017 Tomosyn-1 co-migrates with synapsin and neuropeptide Y markers for SVs and DCVs in live neurons despite lacking a membrane anchor; this vesicular association involves the WD40 and SNARE domains but is not abolished by blockade of synaptotagmin-1 or cognate SNARE interactions Live imaging in mouse hippocampal neurons, genetic blockade of known interactions PloS one Medium 28746398
2023 Synaptotagmin-9 (Syt9) colocalizes and binds with tomosyn-1 and syntaxin-1A to form an inhibitory Syt9-tomosyn-1-Stx1A complex; Syt9 knockdown reduces tomosyn-1 protein via proteasomal degradation, decreasing tomosyn-1 binding to Stx1A and increasing SNARE complex formation and insulin secretion; rescuing tomosyn-1 blocks Syt9-KD-mediated insulin secretion increase Co-immunoprecipitation, proteasome inhibitor treatment, rescue experiment, insulin secretion assay FASEB journal Medium 37432648
2025 Tomosyn-2 interacts with syntaxin-1A to inhibit insulin granule exocytosis by limiting SNARE complex assembly; tomosyn-2 KO mice show improved glucose clearance and enhanced biphasic insulin secretion; loss of tomosyn-2 also reduces beta-cell proliferation and suppresses Akt1 signaling Genetic KO mouse, co-immunoprecipitation, insulin secretion assay from isolated islets, transcriptomic analysis Diabetes Medium 42008692

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process. Neuron 239 9620695
1999 Yeast homologues of tomosyn and lethal giant larvae function in exocytosis and are associated with the plasma membrane SNARE, Sec9. The Journal of cell biology 184 10402465
2006 Tomosyn inhibits synaptic vesicle priming in Caenorhabditis elegans. PLoS biology 129 16895441
2003 The R-SNARE motif of tomosyn forms SNARE core complexes with syntaxin 1 and SNAP-25 and down-regulates exocytosis. The Journal of biological chemistry 107 12782620
2004 Tomosyn inhibits priming of large dense-core vesicles in a calcium-dependent manner. Proceedings of the National Academy of Sciences of the United States of America 84 14983051
2005 PKA-catalyzed phosphorylation of tomosyn and its implication in Ca2+-dependent exocytosis of neurotransmitter. The Journal of cell biology 83 16186257
2004 Structural basis for the inhibitory role of tomosyn in exocytosis. The Journal of biological chemistry 80 15316007
2013 UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans. eLife 74 23951547
2003 Tomosyn interacts with the t-SNAREs syntaxin4 and SNAP23 and plays a role in insulin-stimulated GLUT4 translocation. The Journal of biological chemistry 73 12832401
2014 Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion. The Journal of clinical investigation 69 25244095
2008 Dual inhibition of SNARE complex formation by tomosyn ensures controlled neurotransmitter release. The Journal of cell biology 65 18936251
2004 Regulation of SNAREs by tomosyn and ROCK: implication in extension and retraction of neurites. The Journal of cell biology 63 15240567
2011 Positional cloning of a type 2 diabetes quantitative trait locus; tomosyn-2, a negative regulator of insulin secretion. PLoS genetics 62 21998599
2006 Tomosyn is expressed in beta-cells and negatively regulates insulin exocytosis. Diabetes 53 16505218
2019 LncRNA STXBP5-AS1 suppressed cervical cancer progression via targeting miR-96-5p/PTEN axis. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 52 31212131
2015 CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. Journal of thrombosis and haemostasis : JTH 51 25832887
2007 Tomosyn negatively regulates CAPS-dependent peptide release at Caenorhabditis elegans synapses. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 17881523
2014 Platelet secretion and hemostasis require syntaxin-binding protein STXBP5. The Journal of clinical investigation 46 25244094
2006 Tomosyn-1 is involved in a post-docking event required for pancreatic beta-cell exocytosis. Journal of cell science 46 16787939
2009 Friends and foes in synaptic transmission: the role of tomosyn in vesicle priming. Trends in neurosciences 43 19307030
2005 Two distinct genes drive expression of seven tomosyn isoforms in the mammalian brain, sharing a conserved structure with a unique variable domain. Journal of neurochemistry 40 15659226
2011 Structural and functional analysis of tomosyn identifies domains important in exocytotic regulation. The Journal of biological chemistry 39 21330375
2005 Using microarrays to facilitate positional cloning: identification of tomosyn as an inhibitor of neurosecretion. PLoS genetics 38 16103915
2014 Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arteriosclerosis, thrombosis, and vascular biology 37 24578379
2007 Multiple functional domains are involved in tomosyn regulation of exocytosis. Journal of neurochemistry 36 17666050
2017 SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells. Scientific reports 35 28325894
2007 Receptor-mediated regulation of tomosyn-syntaxin 1A interactions in bovine adrenal chromaffin cells. The Journal of biological chemistry 34 17545156
1999 Three splicing variants of tomosyn and identification of their syntaxin-binding region. Biochemical and biophysical research communications 34 10066450
2017 UNC-18 and Tomosyn Antagonistically Control Synaptic Vesicle Priming Downstream of UNC-13 in Caenorhabditis elegans. The Journal of neuroscience : the official journal of the Society for Neuroscience 33 28821673
2007 Tomosyn negatively regulates both synaptic transmitter and neuropeptide release at the C. elegans neuromuscular junction. The Journal of physiology 31 17627987
2011 Tomosyn-dependent regulation of synaptic transmission is required for a late phase of associative odor memory. Proceedings of the National Academy of Sciences of the United States of America 30 22042858
2019 Long noncoding RNA STXBP5-AS1 inhibits cell proliferation, migration, and invasion through inhibiting the PI3K/AKT signaling pathway in gastric cancer cells. OncoTargets and therapy 27 30881044
2014 Differential interaction of tomosyn with syntaxin and SNAP25 depends on domains in the WD40 β-propeller core and determines its inhibitory activity. The Journal of biological chemistry 27 24782308
2016 Dynamic Partitioning of Synaptic Vesicle Pools by the SNARE-Binding Protein Tomosyn. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 27807164
2015 A Combined Optogenetic-Knockdown Strategy Reveals a Major Role of Tomosyn in Mossy Fiber Synaptic Plasticity. Cell reports 25 26166572
2014 The N- and C-terminal domains of tomosyn play distinct roles in soluble N-ethylmaleimide-sensitive factor attachment protein receptor binding and fusion regulation. The Journal of biological chemistry 24 25063806
2016 Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice. Arteriosclerosis, thrombosis, and vascular biology 23 28062498
2019 Ginsenoside Rg3 and Korean Red Ginseng extract epigenetically regulate the tumor-related long noncoding RNAs RFX3-AS1 and STXBP5-AS1. Journal of ginseng research 22 31700260
2014 Phosphorylation and degradation of tomosyn-2 de-represses insulin secretion. The Journal of biological chemistry 22 25002582
2010 Tomosyn expression pattern in the mouse hippocampus suggests both presynaptic and postsynaptic functions. Frontiers in neuroanatomy 22 21191478
2021 The decoy SNARE Tomosyn sets tonic versus phasic release properties and is required for homeostatic synaptic plasticity. eLife 20 34713802
2021 Ginsenoside Rh2 upregulates long noncoding RNA STXBP5-AS1 to sponge microRNA-4425 in suppressing breast cancer cell proliferation. Journal of ginseng research 20 34764730
2014 Tomosyn-2 is required for normal motor performance in mice and sustains neurotransmission at motor endplates. Brain structure & function 20 24744148
2019 Overexpressed Tomosyn Binds Syntaxins and Blocks Secretion during Pollen Development. Plant physiology 16 31530628
2018 Tomosyn guides SNARE complex formation in coordination with Munc18 and Munc13. FEBS letters 16 29485200
2018 Tomosyn functions as a PKCδ-regulated fusion clamp in mast cell degranulation. Science signaling 16 29970602
2018 Long noncoding RNA STXBP5-AS1 inhibits cell proliferation, migration, and invasion via preventing the PI3K/AKT against STXBP5 expression in non-small-cell lung carcinoma. Journal of cellular biochemistry 15 30450569
2015 Tomosyn is a novel Akt substrate mediating insulin-dependent GLUT4 exocytosis. The international journal of biochemistry & cell biology 14 25725259
2020 Tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors. Journal of neuroscience research 13 32133675
2020 Genetic evidence for an inhibitory role of tomosyn in insulin-stimulated GLUT4 exocytosis. Traffic (Copenhagen, Denmark) 13 32851733
2011 In vivo analysis of conserved C. elegans tomosyn domains. PloS one 13 22022557
2017 Tomosyn associates with secretory vesicles in neurons through its N- and C-terminal domains. PloS one 12 28746398
2014 In vitro reconstitution of Rab GTPase-dependent vesicle clustering by the yeast lethal giant larvae/tomosyn homolog, Sro7. The Journal of biological chemistry 12 25404740
2021 Aberrant hypermethylation induced downregulation of antisense lncRNA STXBP5-AS1 and its sense gene STXBP5 correlate with tumorigenesis of glioma. Life sciences 10 33965377
2018 The tomosyn homologue, Sro7, is a direct effector of the Rab GTPase, Sec4, in post-Golgi vesicle tethering. Molecular biology of the cell 10 29668350
2017 The ubiquitin-proteasome system functionally links neuronal Tomosyn-1 to dendritic morphology. The Journal of biological chemistry 10 29269412
2015 Structural basis for recognition of the Sec4 Rab GTPase by its effector, the Lgl/tomosyn homologue, Sro7. Molecular biology of the cell 10 26202462
2014 Tomosyn interacts with the SUMO E3 ligase PIASγ. PloS one 10 24614299
2017 Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn-1 gene. Brain and behavior 9 28948088
2018 Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients. Thrombosis and haemostasis 8 29972863
2003 WD-40 repeat containing rat lethal giant larvae recessive oncogene, but not m-tomosyn, restores the salt sensitivity in Saccharomyces cerevisiae. International journal of oncology 7 12792798
2023 Tomosyn affects dense core vesicle composition but not exocytosis in mammalian neurons. eLife 6 37695731
2019 A Potential Role for the STXBP5-AS1 Gene in Adult ADHD Symptoms. Behavior genetics 5 30659475
2023 TOM-1/tomosyn acts with the UNC-6/netrin receptor UNC-5 to inhibit growth cone protrusion in Caenorhabditis elegans. Development (Cambridge, England) 4 37014062
2016 Tomosyn Negatively Regulates Arginine Vasopressin Secretion in Embryonic Stem Cell-Derived Neurons. PloS one 4 27732637
2024 The syntaxin-binding protein STXBP5 regulates progerin expression. Scientific reports 3 39379476
2023 Genetic ablation of synaptotagmin-9 alters tomosyn-1 function to increase insulin secretion from pancreatic β-cells improving glucose clearance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 37432648
2017 RESISTIN INHIBITS GLUCOSE-STIMULATED INSULIN SECRETION THROUGH MIR-494 BY TARGET ON STXBP5. Acta endocrinologica (Bucharest, Romania : 2005) 2 31149145
2026 Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis. Diabetes 0 42008692
2025 Tomosyn-2 Regulates Postnatal β-Cell Expansion and Insulin Secretion to Maintain Glucose Homeostasis. bioRxiv : the preprint server for biology 0 40475581
2023 The Role of Tomosyn in the Regulation of Neurotransmitter Release. Advances in neurobiology 0 37615869