Affinage

SNAP25

Synaptosomal-associated protein 25 · UniProt P60880

Length
206 aa
Mass
23.3 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SNAP-25 is a plasma-membrane Q-SNARE that contributes two helices to the SNARE complex it forms with syntaxin and synaptobrevin/VAMP to drive Ca2+-triggered exocytosis of synaptic vesicles and dense-core granules; this role is conserved from the yeast ortholog Sec9, where t-SNARE heterodimerization (Sso1-Sec9) must precede v-SNARE (Snc) engagement (PMID:7954793, PMID:9195974). Botulinum toxin cleavage and null-mouse studies establish SNAP-25 as essential for Ca2+-dependent regulated secretion across endocrine and neuronal cells, with its loss abolishing evoked release while sparing a residual Ca2+-independent spontaneous component (PMID:7896868, PMID:16870728, PMID:17553942); the adult SNAP-25b isoform supports synchronous release and larger primed vesicle pools, underlying a developmental isoform switch (PMID:17728451, PMID:24005294). Stable membrane targeting requires palmitoylation of a central cysteine cluster within residues 85–120 by Golgi and plasma-membrane DHHC enzymes (DHHC2/3/7/15/17), a linker that both accelerates ternary SNARE assembly and engages lipids to promote fusion-pore evolution (PMID:9487128, PMID:10409690, PMID:18579690, PMID:20519516, PMID:30883328). Discrete SNAP-25 surfaces couple the SNARE bundle directly to Ca2+ triggering and to synaptotagmin-1 at two sites governing docking, priming, and fast fusion, while a separate region acts with complexin to clamp spontaneous release (PMID:11830673, PMID:24005294, PMID:27881774, PMID:32698012). SNAP-25 function is tuned by phosphorylation, most notably PKC at Ser-187, which enhances syntaxin binding and is required for postsynaptic NMDA-receptor potentiation (PMID:17325194, PMID:20053906). Beyond canonical exocytosis, SNAP-25 acts as an endosomal Q-SNARE with syntaxin-13 and VAMP2 and recycles via an ARF6-dependent pathway, modulates voltage-gated Ca2+ and K+ channels, and shapes dendritic spine morphology through a postsynaptic complex with p140Cap and PSD-95 (PMID:11978639, PMID:16314394, PMID:16481393, PMID:23868368, PMID:25678324). Disease-causing SNAP25 mutations alter the balance of spontaneous and evoked transmission, demonstrating that dysregulated spontaneous release alone is sufficient to cause developmental and epileptic encephalopathy (PMID:33147442).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Established that the SNAP-25 family functions as a plasma-membrane SNARE partnering with syntaxin and synaptobrevin homologs, defining the conserved exocytic machinery.

    Evidence High-copy suppressor screen, co-IP, and fractionation of yeast Sec9 with Sso1 and Snc1/2

    PMID:7954793 PMID:8089101

    Open questions at the time
    • Did not resolve assembly order of the t-SNARE/v-SNARE complex
    • Inferred from yeast ortholog rather than neuronal SNAP-25
  2. 1995 High

    Showed SNAP-25 is functionally required for regulated secretion beyond neurons, by linking its toxin cleavage to loss of Ca2+-stimulated dense-core granule fusion.

    Evidence Botulinum toxin A/E cleavage and insulin secretion assays in permeabilized pancreatic beta cells

    PMID:7896868

    Open questions at the time
    • Did not define which secretory step (docking, priming, fusion) requires SNAP-25
    • Isoform-specific contributions not addressed
  3. 1997 High

    Resolved the assembly logic of the complex, showing t-SNARE heterodimerization must precede v-SNARE engagement and that the SNAP-25 C-terminus acts post-assembly.

    Evidence In vitro reconstitution with recombinant yeast SNAREs and dominant-negative mutants

    PMID:9195974

    Open questions at the time
    • Post-assembly step not mechanistically defined
    • Performed with yeast proteins
  4. 1999 High

    Defined the membrane-targeting determinant, mapping a minimal palmitoylated domain (residues 85–120) within the inter-helical linker that is necessary and sufficient for plasma-membrane localization.

    Evidence Pulse-chase palmitoylation, brefeldin A treatment, and deletion/heterologous targeting assays

    PMID:10329400 PMID:10409690 PMID:9487128

    Open questions at the time
    • Enzymes catalyzing palmitoylation not yet identified
    • Did not separate targeting from fusion functions of the linker
  5. 2000 High

    Established palmitoylation and syntaxin binding as cooperative contributors to membrane association and identified accessory binding partners that regulate exocytosis.

    Evidence Cysteine mutagenesis with BoNT-resistant reconstitution; yeast two-hybrid and functional overexpression of SNIP and Hrs in PC12 cells

    PMID:10625663 PMID:10825299 PMID:10954418

    Open questions at the time
    • Residual activity of cysteine mutants implies unidentified membrane-association mechanisms
    • SNIP/Hrs interactions are Medium-confidence and lack in vivo loss-of-function validation
  6. 2002 High

    Demonstrated the SNARE complex itself participates directly in Ca2+ triggering and that SNAP-25 domains modulate ion channels, broadening its role beyond fusion catalysis.

    Evidence Site-directed mutagenesis with caged-Ca2+ photolysis in chromaffin cells; patch-clamp with SNAP-25 peptide injection for K+ and L-type Ca2+ channels

    PMID:11830673 PMID:11910352 PMID:11978639

    Open questions at the time
    • Structural basis of cation coordination not resolved
    • Channel-modulation interactions not mapped to specific binding surfaces
  7. 2004 High

    Revealed cell-type-specific SNAP-25 expression and a Ca2+-modulatory function distinguishing GABAergic from glutamatergic neurons.

    Evidence Ca2+ imaging, toxin sensitivity, gain/loss of function, and domain mapping (residues 180–197) in hippocampal cultures

    PMID:14980208

    Open questions at the time
    • Molecular target of the Ca2+-modulatory domain not identified
    • Relationship to channel-modulation findings unresolved
  8. 2005 High

    Identified a recycling and second SNARE function for SNAP-25, showing it traffics via an ARF6-dependent pathway and acts as an endosomal Q-SNARE.

    Evidence Surface labeling/internalization, ARF6 dominant-negative, fractionation, and endosomal SNARE complex co-IP with syntaxin-13/VAMP2 in PC12 cells

    PMID:16314394 PMID:16481393

    Open questions at the time
    • Regulation switching SNAP-25 between exocytic and endosomal pools not defined
    • Physiological significance in neurons not established
  9. 2006 High

    Genetically dissected SNAP-25's contribution to evoked versus spontaneous release using null mice, establishing it as essential for action-potential-dependent transmission.

    Evidence Patch-clamp electrophysiology and FM-dye assays in Snap25-null neurons

    PMID:16870728 PMID:17553942

    Open questions at the time
    • Identity of the SNARE machinery supporting residual spontaneous release unclear
    • Did not address isoform contributions
  10. 2007 High

    Defined isoform- and phosphorylation-dependent tuning of vesicle priming, linking SNAP-25b superiority and Ser-187 phosphorylation to syntaxin binding and pool size.

    Evidence Lentiviral null-rescue with isoforms and S187E phosphomimetic, caged-Ca2+ capacitance, amperometry, and in vitro SNARE binding; secretagogin Ca2+-dependent binding measured by fluorescence

    PMID:16939418 PMID:17325194 PMID:17728451

    Open questions at the time
    • Mechanism by which Ser-187 phosphorylation increases syntaxin affinity not structurally defined
    • Secretagogin interaction lacks functional in vivo validation
  11. 2008 High

    Refined the linker's role, showing a C-terminal hydrophobic stretch is required for fast fusion kinetics and proper fusion-pore behavior.

    Evidence Null-rescue chimera/mutant analysis with caged-Ca2+ capacitance in chromaffin cells

    PMID:18579690

    Open questions at the time
    • Lipid partners of the linker not identified
    • Membrane-curvature mechanism inferred not directly shown
  12. 2010 High

    Established postsynaptic SNARE-dependent roles, showing SNAP-25 mediates kainate-receptor trafficking and PKC-Ser187-dependent NMDA-receptor insertion.

    Evidence Reciprocal co-IP with PICK1/GRIP1/GluK5, intracellular blocking peptides/antibodies, S187A mutagenesis, BoNT, and RNAi with electrophysiology

    PMID:19679075 PMID:20053906 PMID:20519516

    Open questions at the time
    • Vesicular source of postsynaptically inserted receptors not defined
    • How presynaptic and postsynaptic SNAP-25 pools are distinguished unclear
  13. 2011 High

    Linked palmitoylation-site usage and DHHC enzyme specificity to differential subcellular localization, and identified Gβγ binding to the SNAP-25 C-terminus in presynaptic LTD.

    Evidence Palmitoylation-site mutagenesis with confocal localization; toxin cleavage and Gβγ-scavenging peptides with hippocampal imaging/electrophysiology

    PMID:20519516 PMID:21429935 PMID:21633701

    Open questions at the time
    • Dynamics regulating depalmitoylation in vivo not defined
    • Gβγ interaction is Medium-confidence and lacks structural mapping
  14. 2013 High

    Mapped two synaptotagmin-1 binding sites on the SNARE bundle and identified a postsynaptic spine-morphogenesis complex with p140Cap and PSD-95.

    Evidence Mutagenesis in synaptotagmin-1-null rescue with caged-Ca2+ capacitance; co-IP and bidirectional manipulation of spine morphology; LRRK2-Snapin phosphorylation pulldowns

    PMID:23868368 PMID:23949442 PMID:24005294

    Open questions at the time
    • Structural detail of the two synaptotagmin sites not resolved here
    • p140Cap and LRRK2/Snapin findings are Medium-confidence single-lab studies
  15. 2016 High

    Dissected distinct SNAP-25 surface regions controlling priming/spontaneous-clamping versus evoked release probability.

    Evidence Region I/II mutagenesis in null-rescue autaptic neurons plus reconstituted clamping/attachment assays

    PMID:27881774

    Open questions at the time
    • Precise molecular partners at region II not fully defined
    • Interplay with complexin not structurally resolved
  16. 2017 High

    Extended SNAP-25's roles to dense-core vesicle fusion, hair-cell ribbon synapse exocytosis, local axonal translation, and revealed structural basis of Rabphilin-3A/synaptotagmin surface competition.

    Evidence KO-rescue DCV imaging with SNAP homologs; conditional IHC KO with auditory physiology and viral rescue; compartmentalized FUNCAT/FISH; X-ray crystallography of Rabphilin-3A C2B–SNAP-25

    PMID:28404788 PMID:28634303 PMID:28954226 PMID:36483015

    Open questions at the time
    • Why SNAP-47 cannot substitute remains undefined
    • Signals targeting SNAP25 mRNA to presynaptic sites unknown
  17. 2020 High

    Defined the molecular basis of spontaneous-release clamping by complexin on SNAP-25/VAMP2 ends and demonstrated that disease mutations cause encephalopathy through dysregulated spontaneous release.

    Evidence Photo-crosslinking in reconstituted liposomes with autaptic electrophysiology; lentiviral expression of patient mutations in null neurons

    PMID:32698012 PMID:33147442

    Open questions at the time
    • Genotype-phenotype relationships for all mutation clusters not exhaustively mapped
    • Therapeutic implications not addressed
  18. 2023 Medium

    Identified a degradation mechanism, showing TNFAIP1 ubiquitinates SNAP-25 at Lys-69 for proteasomal turnover linked to mitophagy and pyroptosis.

    Evidence Co-IP, K48-linkage-specific ubiquitination assay, K69 mutagenesis, and AAV9 neuronal knockdown with viability/mitophagy assays

    PMID:38102610

    Open questions at the time
    • Single-lab study without independent replication
    • Physiological conditions activating TNFAIP1-mediated degradation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SNAP-25's multiple functions — exocytic SNARE, endosomal SNARE, ion-channel modulator, and postsynaptic spine regulator — are coordinated and spatially partitioned within a single neuron remains unresolved.
  • No unified model linking palmitoylation-controlled localization to functional pool assignment
  • Mechanism switching SNAP-25 between presynaptic and postsynaptic roles unknown
  • Structural basis of channel-modulation interactions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 3 GO:0005794 Golgi apparatus 2
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-9609507 Protein localization 4 R-HSA-392499 Metabolism of proteins 1
Partners
CPLXDLG4RPH3ASRCIN1STX13STX1ASYT1VAMP2
Complex memberships
SNARE complex (syntaxin-1/VAMP2/SNAP-25)endosomal SNARE complex (syntaxin-13/VAMP2/SNAP-25)postsynaptic p140Cap/PSD-95 complex

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Yeast Sec9 (SNAP-25 ortholog) is physically associated with the plasma membrane SNAREs Sso1 (syntaxin homolog) and Snc1 (synaptobrevin homolog), forming a SNARE complex analogous to the neuronal complex; Sec9 is bound to the plasma membrane and absent from post-Golgi vesicles, identifying it as a potential effector of Sec4 GTPase function in exocytosis. High-copy suppressor screen, co-immunoprecipitation, subcellular fractionation Cell High 7954793
1994 Yeast Snc1/2 (synaptobrevin homologs) form a tight physical complex with Sec9 (SNAP-25 homolog) at the plasma membrane, required for fusion of secretory vesicles with the plasma membrane. Genetic interaction analysis, co-immunoprecipitation, subcellular localization The Journal of biological chemistry High 8089101
1995 SNAP-25 is expressed in pancreatic beta cells; botulinum neurotoxins A and E cleave SNAP-25 in these cells and this cleavage is accompanied by inhibition of Ca2+-stimulated insulin secretion, demonstrating SNAP-25 is required for dense-core secretory granule fusion with the plasma membrane in endocrine cells. Western blot, streptolysin-O permeabilization, botulinum toxin cleavage assay, insulin secretion measurement The Journal of cell biology High 7896868
1995 Two alternatively spliced SNAP-25 isoforms (a and b), differing in their putative membrane-interacting domain, localize differently in neurites of transfected PC12 cells, indicating distinct roles in vesicular fusion events during axonal outgrowth versus neurotransmitter release. Transfection, immunofluorescence localization in PC12 cells Proceedings of the National Academy of Sciences of the United States of America Medium 7878010
1997 Biochemical reconstitution of the yeast exocytic SNARE complex shows that neither Sso1 nor Sec9 alone binds Snc1; only the Sso1-Sec9 hetero-oligomeric complex binds Snc1 strongly, revealing that t-SNARE heterodimerization is required before v-SNARE engagement. The C-terminal domain of Sec9 (SNAP-25 homolog) is required for a post-SNARE-assembly step, not SNARE complex formation itself. In vitro reconstitution with recombinant proteins, binding assays, dominant-negative mutant analysis The Journal of biological chemistry High 9195974
1998 SNAP-25 is synthesized as a soluble protein that undergoes palmitoylation ~20 min after synthesis, coinciding with stable membrane association. Disruption of the secretory pathway (brefeldin A) prevents palmitoylation and membrane association of newly synthesized SNAP-25, demonstrating that palmitoylation and plasma membrane targeting require an intact exocytic pathway. Pulse-chase labeling, brefeldin A treatment, membrane fractionation, chemical deacylation in vitro Molecular biology of the cell High 9487128
1999 The minimal plasma membrane-targeting domain of SNAP-25 maps to residues 85–120, which is both necessary and sufficient for plasma membrane targeting of a heterologous protein; this domain contains the palmitoylated cysteine cluster and an additional conserved five-amino-acid sequence required for membrane anchoring, and coincides with the protease-sensitive linker connecting the two SNARE helices. Deletion mapping, heterologous targeting assay, palmitoylation sensitivity to brefeldin A The Journal of biological chemistry High 10409690
1999 SNAP-25 and SNAP-23 are both palmitoylated in vivo on cysteine residues in their central domain; palmitoylation extent correlates with the ability to bind syntaxin in vivo, with SNAP-23 being palmitoylated less efficiently than SNAP-25. In vivo [3H]palmitate labeling, co-immunoprecipitation Biochemical and biophysical research communications Medium 10329400
1999 Sro7p and Sro77p (yeast tomosyn/lethal giant larvae homologs) directly interact with Sec9p (SNAP-25 homolog) both in the cytosol and at the plasma membrane, and can associate with Sec9p within the SNARE complex; genetic analysis places Sro7/Sec9 function downstream of the Rho3 GTPase. Co-immunoprecipitation, subcellular fractionation, genetic epistasis (double mutant analysis) The Journal of cell biology High 10402465
1999 SNAP-25 is phosphorylated by Ca2+/calmodulin-dependent protein kinase II (CaMKII), and SNAP-25 is phosphorylated by cyclic AMP-dependent protein kinase (PKA). Phosphorylation does not directly affect SNARE complex assembly but modulates protein–protein interactions, specifically reducing SNAP-25/syntaxin-4 interaction upon syntaxin-4 phosphorylation by CK II. In vitro kinase assays with purified kinases and recombinant SNARE proteins, co-immunoprecipitation Journal of neurochemistry High 9930733
2000 SNIP (a novel 145-kDa SNAP-25-interacting protein) binds SNAP-25 via coiled-coil interactions; SNIP colocalizes with SNAP-25 and the cortical actin cytoskeleton; overexpression of SNIP or its SNAP-25-binding domain inhibits Ca2+-dependent exocytosis from PC12 cells. Yeast two-hybrid screen, deletion analysis, co-immunoprecipitation, immunofluorescence, exocytosis assay in PC12 cells The Journal of biological chemistry Medium 10625663
2000 Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) specifically interacts with SNAP-25 (but not SNAP-23) via coiled-coil interactions; Hrs colocalizes with SNAP-25 and with dense-core secretory granules and synaptic-like microvesicles in PC12 cells; overexpression of Hrs inhibits Ca2+-dependent exocytosis. Yeast two-hybrid screen, co-immunoprecipitation, confocal immunofluorescence, PC12 exocytosis assay Journal of cell science Medium 10825299
2000 Palmitoylation of SNAP-25 cysteine residues is required for membrane association; progressive cysteine mutations reduce membrane binding; syntaxin 1A can partially re-localize cysteines mutants to the membrane, indicating both palmitoylation and syntaxin binding contribute to membrane association. However, there is a discrepancy between membrane localization and biological activity: even the quadruple cysteine mutant retains minimal secretory activity, suggesting multi-component membrane association. Site-directed mutagenesis of cysteines, subcellular fractionation, BoNT-E resistance reconstitution assay of insulin secretion in HIT cells Journal of cell science High 10954418
2002 Acidic/hydrophilic surface residues of SNAP-25 within the SNARE complex that coordinate divalent cations are directly linked to calcium triggering of exocytosis; reducing net charge at this site in SNAP-25 decreased the steepness of the Ca2+-exocytosis relationship (reducing the number of sequential Ca2+-binding steps by one), identifying the SNARE complex as a direct participant in Ca2+-triggered fusion. Site-directed mutagenesis, chromaffin cell overexpression, UV-flash photolysis of caged Ca2+, patch-clamp capacitance measurements Proceedings of the National Academy of Sciences of the United States of America High 11830673
2002 SNAP-25 inhibits large-conductance Ca2+-activated K+ channels (KCa) and delayed-rectifier K+ channels (KV) in esophageal smooth muscle cells; microinjection of SNAP-25 caused dose-dependent inhibition of outward K+ currents, and BoNT/A cleavage of endogenous SNAP-25 increased outward K+ currents. Patch-clamp electrophysiology, intracellular microinjection of recombinant SNAP-25, BoNT/A intracellular dialysis Gastroenterology Medium 11910352
2002 Distinct domains of SNAP-25 differentially modulate L-type Ca2+ channels (LCa) in pancreatic beta cells: the C-terminal 197–206 residues inhibit LCa, while the NH2-terminal 1–197 domain stimulates LCa. These effects are mediated through the II–III intracellular loop (Lc753-893) of the α1C subunit. Patch-clamp electrophysiology on primary beta cells and HIT cells, intracellular injection of SNAP-25 peptides/truncations, BoNT/A cleavage, competition with recombinant Lc753-893 peptide Diabetes High 11978639
2004 Hippocampal GABAergic synapses lack SNAP-25 and are resistant to BoNT/A and BoNT/E. Exogenous SNAP-25 expression in GABAergic interneurons lowers their Ca2+ responsiveness to depolarization; SNAP-25 silencing in glutamatergic neurons increases Ca2+ elevations; residues 180–197 of SNAP-25 are required for this Ca2+-modulatory function. Immunostaining, BoNT treatment, Ca2+ imaging, viral overexpression/siRNA knockdown, domain deletion analysis (SNAP-25(1-197) vs SNAP-25(1-180)) Neuron High 14980208
2005 SNAP25 recycles from the plasma membrane via an ARF6-regulated, dynamin-independent endocytic pathway; ~20% resides in a perinuclear recycling endosome/TGN compartment. This pathway excludes syntaxin 1A. SNAP25 endosomes merge with clathrin-dependent endosomes containing syntaxin 13. Surface labeling and internalization assay, ARF6 dominant-negative expression, F-actin disruption, subcellular fractionation, immunofluorescence in PC12 cells Molecular biology of the cell Medium 16314394
2006 SNAP25 has a second function as an endosomal Q-SNARE: it forms a complex with syntaxin 13 and VAMP2 on endosomes and is required for trafficking from sorting endosomes to recycling endosomes. BoNT/E expression in PC12 cells redistributed SNAP25 from perinuclear recycling endosomes to sorting endosomes and disrupted endosomal cargo trafficking. BoNT/E light chain expression, siRNA knockdown, immunofluorescence, subcellular fractionation, co-immunoprecipitation of endosomal SNARE complex Molecular biology of the cell High 16481393
2006 SNAP-25-containing SNARE complexes are required for evoked (action potential-dependent) GABA release in developing GABAergic neurons; SNAP-25 null mice lack evoked GABAA-mediated postsynaptic responses while retaining low-level spontaneous AP-independent events. In wild-type hippocampal cultures, SNAP-25 colocalizes with both GABAergic and glutamatergic synaptic markers. Patch-clamp electrophysiology in fetal Snap25-null cortex and hippocampal cultures, immunohistochemistry, FISH, FM-dye synaptic vesicle recycling assay The Journal of neuroscience High 16870728
2007 SNAP-25 deletion leads to near-complete loss of Ca2+-dependent evoked exocytosis while ~10–12% of Ca2+-independent spontaneous release persists; SNAP-25-deficient synapses show no facilitation during high-frequency stimulation and reduced endocytosis during evoked stimulation but normal synaptic vesicle turnover during hypertonic stimulation. Whole-cell patch-clamp, field stimulation, FM-dye uptake/release assay, hypertonic sucrose stimulation in SNAP-25 KO mouse neuronal cultures Journal of neurophysiology High 17553942
2007 SNAP-25b but not SNAP-23 supports synchronous Ca2+-triggered neurotransmitter release; SNAP-23 supports only asynchronous release resembling synaptotagmin-1 null phenotype. SNAP-25b is superior to SNAP-25a in vesicle priming (larger readily releasable pool), consistent with a developmental role for the isoform switch. Lentiviral rescue of SNAP-25 null mouse neurons with individual isoforms, whole-cell patch-clamp, hypertonic sucrose vesicle pool measurements The Journal of neuroscience High 17728451
2007 Phosphomimetic SNAP-25 S187E mutation increases the highly Ca2+-sensitive pool (HCSP) of vesicles ~3-fold and increases syntaxin binding in vitro while decreasing Ca2+-independent synaptotagmin I binding; the enhancement of HCSP correlates with increased syntaxin binding rather than synaptotagmin I binding. Semliki Forest Virus expression in bovine chromaffin cells, UV-flash photolysis of caged Ca2+, patch-clamp capacitance, carbon-fiber amperometry, in vitro SNARE binding assay The Journal of general physiology High 17325194
2007 Secretagogin, a hexa EF-hand Ca2+-binding protein, binds SNAP-25 with Kd ~120 nM in the presence of Ca2+ and ~1.5 µM in its absence, as identified from brain and insulinoma cell lysates; this Ca2+-dependent interaction suggests secretagogin links Ca2+ signaling to exocytotic processes. Affinity purification from brain/insulinoma lysates, mass spectrometry identification, Kd measurement by fluorescence The Biochemical journal Medium 16939418
2008 The SNAP-25 linker domain mediates membrane association via palmitoylated cysteines and a 10-amino-acid hydrophobic/charged stretch in the C-terminal half of the linker required for fast exocytosis; absence of this stretch slows fusion rate, prolongs fusion pore duration, and shifts Ca2+ dependence toward higher concentrations. SNAP-25 null chromaffin cell rescue with linker chimeras/mutants, patch-clamp capacitance, UV-flash photolysis of caged Ca2+ Molecular biology of the cell High 18579690
2009 SNAP25 is critical for synaptic removal of kainate receptors (KARs): it co-immunoprecipitates with PICK1, GRIP1, and GluK5 (KA2) subunits; intracellular SNAP25 antibodies/blocking peptides cause GluK5-dependent run-up of KAR-mediated EPSCs and prevent activity-dependent LTD of KAR EPSCs. The SNAP25/PICK1/GluK5 interaction is regulated by PKC. Co-immunoprecipitation from hippocampal neurons and HEK293 cells, patch-clamp of CA3 pyramidal neurons in hippocampal slices with intracellular antibody/peptide delivery, PKC pharmacology Neuron High 19679075
2010 PKC phosphorylates SNAP-25 at Ser-187; constitutively active PKC-dependent potentiation of NMDAR currents requires intact SNAP-25 and is abolished by S187A mutation, RNAi against SNAP-25, BoNT/A, BoNT/B, or SNAP-25 C-terminal blocking peptide, identifying SNAP-25 Ser-187 as the PKC target critical for SNARE-dependent postsynaptic NMDAR insertion. Whole-cell patch-clamp in hippocampal neurons, RNAi knockdown, site-directed mutagenesis (S187A), BoNT treatment, intracellular peptide delivery, mossy fiber-CA3 EPSC recording The Journal of neuroscience High 20053906
2010 DHHC3, DHHC7, and DHHC17 (Golgi-localized palmitoyl transferases) promote membrane association and palmitoylation of all SNAP25/23 isoforms; DHHC15 selectively palmitoylates SNAP25b but not SNAP23 or SNAP25a, and this specificity is determined by the cysteine-rich domain sequence rather than the DHHC domain alone; DHHC2 palmitoylates all SNAP25/23 isoforms at the plasma membrane. DHHC overexpression in HEK cells, metabolic [3H]palmitate labeling, membrane fractionation, point mutagenesis of cysteine domain, domain-swap chimeras, growth hormone secretion assay The Journal of biological chemistry High 20519516
2011 Palmitoylation of specific SNAP25 cysteine residues determines its precise intracellular distribution: mutating individual palmitoylation sites enhances SNAP25 association with recycling endosomes and TGN; the cysteine-rich domain dominantly directs intracellular patterning, and dynamic palmitoylation regulates dual localization at the plasma membrane and endosomes. Site-directed palmitoylation-site mutagenesis, confocal immunofluorescence, CAAX-fusion chimera comparison, subcellular fractionation in PC12 cells Journal of cell science Medium 21429935
2011 The C-terminus of SNAP-25 is required for LTD (but not LTP) of synaptic transmission; Gβγ binds the C-terminus of SNAP-25 and mediates both transient presynaptic inhibition and induction of presynaptic LTD. Scavenging Gβγ with the SNAP-25 C-terminal peptide or mSIRK blocked LTD. Two-photon Ca2+ imaging, electrophysiology in hippocampal slices, BoNT/A cleavage of SNAP-25 C-terminus, presynaptic electroporation of blocking peptides PloS one Medium 21633701
2013 Synaptotagmin-1 interacts with two sites on SNAP-25 within the SNARE bundle: a central domain (around layer zero, covering both SNARE motifs) essential for vesicle docking, priming, and fast fusion triggering; and a C-terminal domain with a subsidiary role in triggering required for full readily releasable pool size. Mutation of these sites causes no additional phenotype in synaptotagmin-1-null cells, confirming mechanistic relevance. SNAP-25B supports stronger synaptotagmin-1 interactions than SNAP-25A, explaining the larger primed vesicle pool with the adult isoform. Site-directed mutagenesis, patch-clamp capacitance measurements in chromaffin cells, UV-flash photolysis of caged Ca2+, synaptotagmin-1 KO background rescue The Journal of neuroscience High 24005294
2013 SNAP-25 interacts with the postsynaptic adaptor p140Cap via its plasma membrane-binding capacity; acute SNAP-25 reduction causes immature dendritic spine phenotype, and overexpression increases density of mature PSD-95-positive spines; this postsynaptic role requires SNAP-25 binding to both the plasma membrane and p140Cap. siRNA knockdown, lentiviral overexpression, co-immunoprecipitation, confocal imaging of spine morphology in hippocampal neurons Nature communications Medium 23868368
2013 LRRK2 phosphorylates Snapin at Thr-117; phosphomimetic Snapin T117D reduces Snapin binding to SNAP-25 (GST pulldown) and decreases synaptotagmin interaction with the SNARE complex; LRRK2-dependent Snapin phosphorylation in hippocampal neurons reduces the number of readily releasable vesicles and exocytotic release. In vitro kinase assay, GST pulldown, co-immunoprecipitation from rat brain lysate, site-directed mutagenesis, live-cell exocytosis assay in hippocampal neurons Experimental & molecular medicine Medium 23949442
2015 SNAP-25 is part of a postsynaptic molecular complex including PSD-95 and p140Cap in brain; p140Cap binds both SNAP-25 and PSD-95; in vivo SNAP-25 knockdown in CA1 reduces spine number and impairs PSD-95 dynamics. Co-immunoprecipitation from brain tissue, in vivo lentiviral knockdown, live FRAP imaging of PSD-95 in hippocampal neurons, confocal spine density quantification Cell death and differentiation Medium 25678324
2016 SNAP-25 region I (centered on D166) is required for vesicle priming via synaptotagmin-1 interaction and for clamping spontaneous release in concert with complexin; SNAP-25 region II (D51/E52/E55) is required for evoked release probability. Combining both region I+II mutations abrogates evoked release. Region I mutations unclamped spontaneous release correlating with defective complexin clamping in vitro. Site-directed mutagenesis of SNAP-25, autaptic neuron electrophysiology in SNAP-25 null background rescue, in vitro t-SNARE vesicle attachment assay, reconstituted fusion clamping assay The Journal of neuroscience High 27881774
2017 Crystal structure of Rabphilin-3A C2B domain in complex with SNAP-25 reveals that Rabphilin-3A contacts the same SNAP-25 surface as synaptotagmin-1 but uses a unique structural element; PIP2 and Ca2+ cooperate with SNAP-25 binding to allow plasma membrane docking in a conformation compatible with the full SNARE complex. X-ray crystallography of C2B-SNAP25 and C2B-PIP2 complexes, biochemical binding analyses Proceedings of the National Academy of Sciences of the United States of America High 28634303
2017 SNAP-25 is required for dense-core vesicle (DCV) fusion in hippocampal neurons from DIV4 onward (developmental switch); SNAP-23 can rescue DCV and synaptic vesicle fusion and neuronal survival in SNAP-25 KO neurons more efficiently than SNAP-29; SNAP-47 cannot substitute for SNAP-25 in DCV or SV fusion. SNAP-25 KO mouse neuronal cultures, lentiviral rescue with SNAP-23/29/47, live-cell DCV exocytosis imaging (neuropeptide-Venus), electrophysiology Journal of cell science High 28404788
2017 Local intra-axonal synthesis of SNAP25 is required for presynaptic terminal assembly: SNAP25 mRNA is recruited to nascent presynaptic sites and locally translated; inhibition of intra-axonal SNAP25 synthesis impairs SNAP25 clustering and other presynaptic protein clustering, and reduces synaptic vesicle release. Compartmentalized axon culture, local protein synthesis inhibition, fluorescent non-canonical amino acid tagging (FUNCAT) of newly synthesized proteins, SNAP25 mRNA FISH at presynaptic sites, synaptic vesicle release assay Cell reports High 28954226
2017 SNAP-25 is essential for normal exocytosis at inner hair cell ribbon synapses: conditional Snap-25 knockout in IHCs causes severe deafness due to defective IHC exocytosis followed by ribbon degeneration and IHC loss; viral transfer of Snap-25 rescues hearing and IHC exocytosis. Conditional KO mouse (AAV-Cre in IHCs), auditory brainstem response, IHC whole-cell patch-clamp capacitance measurement, immunostaining, viral rescue iScience High 36483015
2019 The SNAP-25 linker domain supports fusion intermediates through two synergistic functions: (1) facilitating t-SNARE interactions and accelerating ternary SNARE complex assembly, and (2) the acylated N-terminal linker segment engages in local lipid interactions to facilitate fusion triggering and fusion pore evolution, putatively by affecting membrane curvature. Structure-function analysis with linker mutants in SNAP-25 null chromaffin cells, patch-clamp capacitance, carbon-fiber amperometry, in vitro SNARE assembly assay eLife High 30883328
2020 The accessory helix of complexin suppresses spontaneous exocytosis by laterally binding the membrane-proximal C-terminal ends of SNAP-25 and VAMP2 (prior to fusion), restraining final SNARE bundle zippering; complexin interface mutants that disrupt these contacts selectively increase spontaneous neurotransmitter release in neurons. Reconstituted fusion assay, site-specific photo-crosslinking in liposome system, autaptic neuron electrophysiology with complexin mutants Cell reports High 32698012
2020 Disease-causing SNAP25 mutations associated with developmental and epileptic encephalopathies alter synaptic transmission; structurally clustered mutations produce related transmission phenotypes; one specific mutation augments spontaneous neurotransmitter release without altering evoked release, demonstrating that aberrant spontaneous release alone is sufficient to cause disease. Lentiviral expression of patient mutations in snap-25 null mouse neurons, whole-cell patch-clamp (spontaneous and evoked release) Neuron High 33147442
2023 The ubiquitin ligase TNFAIP1 targets SNAP25 for K48-linked polyubiquitination at Lys-69, leading to SNAP25 proteasomal degradation; the N-terminal region (residues 1–96) of TNFAIP1 forms the conjugate with SNAP25; TNFAIP1 knockdown stabilizes SNAP25 and protects against mitophagy impairment and pyroptosis. Co-immunoprecipitation, ubiquitination assay with K48-linkage-specific analysis, site-directed mutagenesis (K69 target), AAV9 neuronal knockdown, cell viability and mitophagy assays Cell communication and signaling Medium 38102610

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Sec9 is a SNAP-25-like component of a yeast SNARE complex that may be the effector of Sec4 function in exocytosis. Cell 328 7954793
1995 SNAP-25 is expressed in islets of Langerhans and is involved in insulin release. The Journal of cell biology 215 7896868
1995 Differential expression of SNAP-25 protein isoforms during divergent vesicle fusion events of neural development. Proceedings of the National Academy of Sciences of the United States of America 200 7878010
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
2004 SNAP-25 modulation of calcium dynamics underlies differences in GABAergic and glutamatergic responsiveness to depolarization. Neuron 182 14980208
1998 SNAP-25 palmitoylation and plasma membrane targeting require a functional secretory pathway. Molecular biology of the cell 164 9487128
2016 SNAP-25, a Known Presynaptic Protein with Emerging Postsynaptic Functions. Frontiers in synaptic neuroscience 154 27047369
1999 Differential phosphorylation of syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25) isoforms. Journal of neurochemistry 151 9930733
2002 The SNARE protein SNAP-25 is linked to fast calcium triggering of exocytosis. Proceedings of the National Academy of Sciences of the United States of America 128 11830673
2007 Differential abilities of SNAP-25 homologs to support neuronal function. The Journal of neuroscience : the official journal of the Society for Neuroscience 108 17728451
2010 Palmitoylation of the SNAP25 protein family: specificity and regulation by DHHC palmitoyl transferases. The Journal of biological chemistry 105 20519516
2010 SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. The Journal of neuroscience : the official journal of the Society for Neuroscience 102 20053906
2007 Differential effects of SNAP-25 deletion on Ca2+ -dependent and Ca2+ -independent neurotransmission. Journal of neurophysiology 102 17553942
1999 SNAP-25 is targeted to the plasma membrane through a novel membrane-binding domain. The Journal of biological chemistry 99 10409690
2019 SNAP-25 in Serum Is Carried by Exosomes of Neuronal Origin and Is a Potential Biomarker of Alzheimer's Disease. Molecular neurobiology 98 30680692
2009 SNAP-25 in neuropsychiatric disorders. Annals of the New York Academy of Sciences 98 19161380
2006 Expression and function of SNAP-25 as a universal SNARE component in GABAergic neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 97 16870728
1997 Syndet is a novel SNAP-25 related protein expressed in many tissues. Journal of cell science 96 9067602
1997 Analysis of a yeast SNARE complex reveals remarkable similarity to the neuronal SNARE complex and a novel function for the C terminus of the SNAP-25 homolog, Sec9. The Journal of biological chemistry 95 9195974
1999 Cultured glial cells express the SNAP-25 analogue SNAP-23. Glia 94 10417817
2000 SNIP, a novel SNAP-25-interacting protein implicated in regulated exocytosis. The Journal of biological chemistry 84 10625663
1999 SNAP-23 and SNAP-25 are palmitoylated in vivo. Biochemical and biophysical research communications 84 10329400
2007 Binding of calcium ions and SNAP-25 to the hexa EF-hand protein secretagogin. The Biochemical journal 81 16939418
2009 A role for SNAP25 in internalization of kainate receptors and synaptic plasticity. Neuron 80 19679075
2018 The SNAP-25 Protein Family. Neuroscience 76 30267828
2015 Association between SNAP-25 gene polymorphisms and cognition in autism: functional consequences and potential therapeutic strategies. Translational psychiatry 74 25629685
2002 Modulation of L-type Ca(2+) channels by distinct domains within SNAP-25. Diabetes 70 11978639
2013 Synaptotagmin interaction with SNAP-25 governs vesicle docking, priming, and fusion triggering. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 24005294
2007 Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington's disease. Journal of neurochemistry 69 17877635
2012 Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs. Cerebral cortex (New York, N.Y. : 1991) 67 23064108
2017 Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals. Cell reports 66 28954226
2015 Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis. Cell death and differentiation 63 25678324
2013 SNAP-25 regulates spine formation through postsynaptic binding to p140Cap. Nature communications 63 23868368
1992 Differential expression of the presynaptic protein SNAP-25 in mammalian retina. Journal of neuroscience research 63 1453474
2004 SNAP-25 in hippocampal CA1 region is involved in memory consolidation. The European journal of neuroscience 62 15355326
2005 Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience 60 15749336
2020 Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies. Neuron 59 33147442
2013 Reduced SNAP-25 alters short-term plasticity at developing glutamatergic synapses. EMBO reports 58 23732542
1996 Expression of synaptosomal-associated protein SNAP-25 in endocrine anterior pituitary cells. European journal of cell biology 58 8741217
1993 Multiple loci for synapse protein SNAP-25 in the tetraploid goldfish. Proceedings of the National Academy of Sciences of the United States of America 58 8248151
2013 miR-153 regulates SNAP-25, synaptic transmission, and neuronal development. PloS one 57 23451149
2002 A Drosophila SNAP-25 null mutant reveals context-dependent redundancy with SNAP-24 in neurotransmission. Genetics 55 12242238
2007 Phosphomimetic mutation of Ser-187 of SNAP-25 increases both syntaxin binding and highly Ca2+-sensitive exocytosis. The Journal of general physiology 52 17325194
2019 SNAP-25 isoforms differentially regulate synaptic transmission and long-term synaptic plasticity at central synapses. Scientific reports 51 31024034
2013 LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25. Experimental & molecular medicine 50 23949442
2016 Interactions Between SNAP-25 and Synaptotagmin-1 Are Involved in Vesicle Priming, Clamping Spontaneous and Stimulating Evoked Neurotransmission. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 27881774
2017 SNAP-25 gene family members differentially support secretory vesicle fusion. Journal of cell science 47 28404788
2008 Heterogeneous expression of SNAP-25 in rat and human brain. The Journal of comparative neurology 47 18041776
2011 Differential palmitoylation regulates intracellular patterning of SNAP25. Journal of cell science 46 21429935
2000 Membrane localization and biological activity of SNAP-25 cysteine mutants in insulin-secreting cells. Journal of cell science 46 10954418
1999 Differential expression of SNAP-25 isoforms and SNAP-23 in the adrenal gland. Journal of neurochemistry 46 9886089
2017 Early Golgi Abnormalities and Neurodegeneration upon Loss of Presynaptic Proteins Munc18-1, Syntaxin-1, or SNAP-25. The Journal of neuroscience : the official journal of the Society for Neuroscience 44 28348137
2015 Botulinum neurotoxin type A: Actions beyond SNAP-25? Toxicology 44 26169827
2006 A second SNARE role for exocytic SNAP25 in endosome fusion. Molecular biology of the cell 43 16481393
2016 A review of the role of synaptosomal-associated protein 25 (SNAP-25) in neurological disorders. The International journal of neuroscience 42 27734716
1997 Functional importance of synaptobrevin and SNAP-25 during exocytosis of histamine by rat gastric enterochromaffin-like cells. Endocrinology 42 9389539
2018 Nanobodies reveal an extra-synaptic population of SNAP-25 and Syntaxin 1A in hippocampal neurons. mAbs 41 30466346
1994 Yeast Snc proteins complex with Sec9. Functional interactions between putative SNARE proteins. The Journal of biological chemistry 41 8089101
2011 Differential expression of SNAP-25 family proteins in the mouse brain. The Journal of comparative neurology 40 21280044
2011 Gβγ and the C terminus of SNAP-25 are necessary for long-term depression of transmitter release. PloS one 40 21633701
2022 CSF levels of SNAP-25 are increased early in Creutzfeldt-Jakob and Alzheimer's disease. Journal of neurology, neurosurgery, and psychiatry 39 35995553
2003 Elevated cerebrospinal fluid SNAP-25 in schizophrenia. Biological psychiatry 39 12814864
1998 SNAP-25. The international journal of biochemistry & cell biology 39 9785471
2017 Structural characterization of the Rabphilin-3A-SNAP25 interaction. Proceedings of the National Academy of Sciences of the United States of America 36 28634303
2020 Complexin Suppresses Spontaneous Exocytosis by Capturing the Membrane-Proximal Regions of VAMP2 and SNAP25. Cell reports 35 32698012
2009 AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity. Journal of neurochemistry 35 20002519
2005 SNAP25, but not syntaxin 1A, recycles via an ARF6-regulated pathway in neuroendocrine cells. Molecular biology of the cell 35 16314394
2003 Neuron cell type-specific SNAP-25 expression driven by multiple regulatory elements in the nematode Caenorhabditis elegans. Journal of molecular biology 35 14529613
2000 Hrs interacts with SNAP-25 and regulates Ca(2+)-dependent exocytosis. Journal of cell science 34 10825299
2022 Quantification of SNAP-25 with mass spectrometry and Simoa: a method comparison in Alzheimer's disease. Alzheimer's research & therapy 33 35659284
2021 SNAP25 Inhibits Glioma Progression by Regulating Synapse Plasticity via GLS-Mediated Glutaminolysis. Frontiers in oncology 32 34490096
2011 Regional and developmental brain expression patterns of SNAP25 splice variants. BMC neuroscience 32 21526988
2008 The SNAP-25 linker as an adaptation toward fast exocytosis. Molecular biology of the cell 32 18579690
2005 Promiscuous interaction of SNAP-25 with all plasma membrane syntaxins in a neuroendocrine cell. The Biochemical journal 32 15975093
2019 SNAP-25 in Major Psychiatric Disorders: A Review. Neuroscience 31 30790667
1999 CSF SNAP-25 in schizophrenia and bipolar illness. A pilot study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 31 10633477
2017 Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice. Neural plasticity 30 29318050
2023 Neuronal-specific TNFAIP1 ablation attenuates postoperative cognitive dysfunction via targeting SNAP25 for K48-linked ubiquitination. Cell communication and signaling : CCS 29 38102610
2008 SNAP-25 gene polymorphisms and weight gain in schizophrenic patients. Journal of psychiatric research 29 18191416
2002 SNAP-25, a SNARE protein, inhibits two types of K channels in esophageal smooth muscle. Gastroenterology 29 11910352
2005 A fission yeast SNAP-25 homologue, SpSec9, is essential for cytokinesis and sporulation. Cell structure and function 28 16272747
1997 Intracellular location of SNAP-25 in human neutrophils. Biochemical and biophysical research communications 28 9344876
2014 SNAP25 ameliorates sensory deficit in rats with spinal cord transection. Molecular neurobiology 27 24519330
2017 MicroRNA miR-27 Inhibits Adenovirus Infection by Suppressing the Expression of SNAP25 and TXN2. Journal of virology 26 28356525
1998 Differential turnover of syntaxin and SNAP-25 during synaptogenesis in cultured cerebellar granule neurons. Journal of neuroscience research 26 9753195
2019 Serum miRNAs Expression and SNAP-25 Genotype in Alzheimer's Disease. Frontiers in aging neuroscience 24 30914946
2007 Thyroid hormone regulates the expression of SNAP-25 during rat brain development. Molecular and cellular biochemistry 23 17909947
2009 Distribution of the SNAP25 and SNAP23 synaptosomal-associated protein isoforms in rat cerebellar cortex. Neuroscience 22 19735702
2002 Identification of a novel SNAP25 interacting protein (SIP30). Journal of neurochemistry 22 12068081
2002 Molecular analysis of SNAP-25 function in exocytosis. Annals of the New York Academy of Sciences 22 12438121
1997 Complex gene organization of synaptic protein SNAP-25 in Drosophila melanogaster. Gene 22 9272858
2022 The SNARE protein SNAP-25 is required for normal exocytosis at auditory hair cell ribbon synapses. iScience 21 36483015
2021 Sarcopenia associates with SNAP-25 SNPs and a miRNAs profile which is modulated by structured rehabilitation treatment. Journal of translational medicine 21 34289870
2019 The SNAP-25 linker supports fusion intermediates by local lipid interactions. eLife 21 30883328
2014 Association of SNAP-25, SLC6A2, and LPHN3 with OROS methylphenidate treatment response in attention-deficit/hyperactivity disorder. Clinical neuropharmacology 21 25229170
2010 Regulation of SNAP-25 trafficking and function by palmitoylation. Biochemical Society transactions 21 20074052
2001 NGF enhances depolarization effects on SNAP-25 expression: induction of SNAP-25b isoform. Neuroreport 21 11277561
1999 Proteolysis of synaptobrevin, syntaxin, and SNAP-25 in alveolar epithelial type II cells. IUBMB life 20 10632578
2025 SNAP-25: A biomarker of synaptic loss in neurodegeneration. Clinica chimica acta; international journal of clinical chemistry 19 40058720
2016 Synaptosome-Associated Protein 25 (SNAP25) Gene Association Analysis Revealed Risk Variants for ASD, in Iranian Population. Journal of molecular neuroscience : MN 19 27888397

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