Affinage

SYT1

Synaptotagmin-1 · UniProt P21579

Length
422 aa
Mass
47.6 kDa
Annotated
2026-06-10
40 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SYT1 (synaptotagmin-1) is a presynaptic Ca²⁺ sensor that triggers fast, synchronous neurotransmitter release through its tandem C2A and C2B domains, which engage the SNARE complex and membrane phospholipids via conserved polybasic patches [PMID:bio_10.1101_2024.09.12.612660, PMID:bio_10.1101_2025.09.30.679486]. At fast inhibitory synapses SYT1 functions redundantly with SYT2 as the evoked-release Ca²⁺ sensor, with loss of both required to desynchronize and reduce release (PMID:28363983). Beyond fusion triggering, SYT1 controls vesicle docking and fusion pore dynamics — neutralization of its C2A/C2B polybasic patches impairs dense-core-vesicle docking and produces enlarged, faster-releasing fusion pores [PMID:bio_10.1101_2024.09.12.612660]. SYT1 also governs its own endocytic retrieval: its C2B domain binds SV2A to form surface nanoclusters that limit dynamin-1 recruitment and tune the rate of SYT1 entry into recycling vesicles (PMID:39091022), and efficient clathrin-mediated endocytic sorting of SYT1 depends on its interaction with STON2 (PMID:38402028). The SV2-SYT1 nanocluster is hijacked as the entry route for botulinum neurotoxins A and E into synaptic vesicles (PMID:37226896). De novo heterozygous missense variants across the C2A and C2B domains cause a dominant-negative impairment of evoked exocytosis whose magnitude correlates quantitatively with neurodevelopmental severity in affected individuals (Baker-Gordon syndrome) (PMID:30107533, PMID:39481209). Emerging non-neuronal roles in late endo-lysosomal/MR1 vesicle trafficking and macrophage phagocytosis have been described but are not yet well characterized in the available corpus [PMID:bio_10.1101_2025.06.23.660389, PMID:bio_10.1101_2025.11.24.690103].

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2017 High

    Established which Ca²⁺ sensor drives fast evoked release at inhibitory synapses, resolving whether SYT1 acts alone or redundantly.

    Evidence Conditional and conventional Syt1/Syt2 knockout mice with optical stimulation and electrophysiology at glycinergic and GABAergic synapses

    PMID:28363983

    Open questions at the time
    • Does not resolve the molecular basis of redundancy between SYT1 and SYT2
    • Excitatory synapse dependence not addressed in this study
  2. 2018 High

    Linked C2B-domain SYT1 missense variants to a dominant-negative human disease mechanism, distinguishing exocytic from endocytic defects.

    Evidence Expression of five rat SYT1 C2B mutants in mouse hippocampal cultures with live imaging of localization and synaptic vesicle kinetics

    PMID:30107533

    Open questions at the time
    • Mechanism by which mutant SYT1 dominantly interferes with wild-type protein not defined at molecular level
    • Only C2B variants tested
  3. 2023 High

    Showed that botulinum neurotoxins exploit the preassembled SV2-SYT1 nanocluster for endocytic entry into synaptic vesicles.

    Evidence Super-resolution imaging and EM of inactivated BoNT/A in hippocampal neurons plus SYT1 CRISPRi knockdown with SNAP-25 cleavage readout

    PMID:37226896

    Open questions at the time
    • Stoichiometry of the PSG-SYT1-SV2 toxin complex not resolved
    • Generalizability to other BoNT serotypes beyond A and E untested
  4. 2024 High

    Defined the SV2A-dependent C2B nanoclustering mechanism that segregates SYT1 from endocytic machinery and sets its recycling rate.

    Evidence Single-molecule imaging, C2B point mutations, SV2A knockdown, and dynamin-1 recruitment / Rab5 sorting assays in hippocampal neurons

    PMID:39091022

    Open questions at the time
    • Whether nanoclustering also modulates the exocytic Ca²⁺-sensing function not addressed
    • Structural basis of the C2B-SV2A interface not determined
  5. 2024 High

    Extended the disease-variant catalog to C2A-domain positions and quantitatively tied exocytic impairment to clinical severity.

    Evidence SYT1-pHluorin evoked exocytosis assays in hippocampal neurons across eight C2A and C2B variants

    PMID:39481209

    Open questions at the time
    • Does not separate fusion-triggering defects from docking or endocytic contributions per variant
    • In vivo neurodevelopmental correlate not modeled
  6. 2024 Medium

    Connected SYT1 endocytic sorting to a STON2-dependent pathway with disease and pharmacological relevance.

    Evidence Co-immunoprecipitation, STON2 knockin mouse electrophysiology, Syt1 sorting assay, and haloperidol rescue

    PMID:38402028

    Open questions at the time
    • Single-lab Co-IP without reciprocal structural mapping of the STON2-SYT1 interface
    • Direct causal link between Syt1 mis-sorting and behavioral phenotype not established
  7. 2024 Medium

    Assigned the C2A/C2B polybasic patches to vesicle docking and fusion pore regulation, separating these roles from Ca²⁺ binding.

    Evidence Polybasic-patch mutagenesis with DCV docking and single-vesicle serotonin release measurements in a human neuroendocrine cell line (preprint)

    PMID:bio_10.1101_2024.09.12.612660

    Open questions at the time
    • Preprint, single lab
    • Neuroendocrine DCV findings not validated at central synapses
  8. 2025 Low

    Reported non-neuronal SYT1 functions in endo-lysosomal/MR1 trafficking and macrophage phagocytosis.

    Evidence Immunofluorescence localization and Syt1 loss/overexpression with MR1-MAIT and phagocytosis functional assays (preprints)

    PMID:bio_10.1101_2025.06.23.660389 PMID:bio_10.1101_2025.11.24.690103

    Open questions at the time
    • Overexpression and single functional readouts in preprints
    • Molecular partners mediating non-neuronal roles unidentified
    • Physiological relevance untested in vivo
  9. 2025 Medium

    Dissected C2B-SNARE and polybasic-motif contributions to evoked versus spontaneous release using an invertebrate ortholog.

    Evidence AlphaFold3 modeling, mutagenesis, and electrophysiology at the C. elegans NMJ (preprint, ortholog SNT-1)

    PMID:bio_10.1101_2025.09.30.679486

    Open questions at the time
    • Ortholog study, preprint
    • Multiple SNARE-binding pathways for spontaneous release not individually resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the disease variants dominantly poison wild-type SYT1 function and whether the non-neuronal trafficking roles are conserved physiological functions remain unresolved.
  • No structural model of the dominant-negative interference mechanism
  • Non-neuronal roles rest only on preprint overexpression/loss-of-function data
  • Direct partners for endo-lysosomal SYT1 unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005764 lysosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1500931 Cell-Cell communication 1
Partners
DNM1SNAP25STON2SV2A
Complex memberships
SNARE complexSV2-SYT1 surface nanocluster

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 De novo heterozygous missense mutations in the SYT1 C2B domain (M303K, D304G, D366E, I368T, N371K) cause a dominant-negative impairment of synaptic vesicle exocytosis; SYT1D304G and SYT1D366E fail to relocalize to nerve terminals following stimulation, indicating defective endocytic retrieval, while all variants slow exocytic rate following sustained action potential stimulation in hippocampal neurons. Expression of rat SYT1 mutants in wild-type mouse primary hippocampal cultures; live imaging of SYT1 localization at rest and after stimulation; synaptic vesicle kinetics assays Brain : a journal of neurology High 30107533
2024 Pathogenic SYT1 variants in both the C2A domain (L159R, T196K, E209K, E219Q) and additional C2B domain positions (M303V, S309P, Y365C, G369D) cause a graded, variant-dependent dominant-negative impairment of evoked exocytosis; the extent of exocytic impairment correlates quantitatively with the severity of neurodevelopmental outcomes in affected individuals. Cultured hippocampal neurons transfected with SYT1-pHluorin; measurement of evoked exocytosis for each variant EBioMedicine High 39481209
2024 SYT1 forms surface nanoclusters on the neuronal plasma membrane through interaction of its C2B domain with SV2A; this nanoclustering is disrupted by the Syt1K326A/K328A mutation or SV2A knockdown. SV2A-Syt1 nanoclustering segregates SYT1 from the endocytic machinery by limiting dynamin-1 recruitment, thereby negatively regulating the rate of SYT1 entry into recycling synaptic vesicles. Single-molecule imaging in hippocampal neurons; C2B domain point mutations; SV2A knockdown; dynamin-1 recruitment assay; Rab5 sorting assay Journal of neurochemistry High 39091022
2023 Targeted endocytosis of botulinum neurotoxin type A (BoNT/A) into synaptic vesicles requires simultaneous binding to a preassembled PSG-SYT1 complex and SV2 on the neuronal plasma membrane, facilitating SYT1-SV2 nanoclustering that controls endocytic sorting of the toxin; SYT1 CRISPRi knockdown suppressed BoNT/A- and BoNT/E-induced neurointoxication (SNAP-25 cleavage). Live-cell super-resolution imaging and electron microscopy of catalytically inactivated BoNT/A wildtype and receptor-binding-deficient mutants in hippocampal neurons; SYT1 CRISPRi knockdown with SNAP-25 cleavage readout The EMBO journal High 37226896
2017 At fast-releasing inhibitory synapses (MNTB-LSO glycinergic and basket/stellate-Purkinje GABAergic), SYT1 and SYT2 are co-expressed and function redundantly as Ca2+ sensors for evoked transmitter release; genetic inactivation of both Syt1 and Syt2 is required to significantly reduce and desynchronize fast release, whereas Syt2 KO alone has only minor effects. Conditional and conventional knockout mouse lines; viral Cre expression; optical stimulation; electrophysiological recording; immunohistochemistry The Journal of neuroscience : the official journal of the Society for Neuroscience High 28363983
2024 STON2 (Stonin 2) dephosphorylation caused by schizophrenia-related variants reduces its interaction with SYT1, impairing clathrin-mediated endocytosis (CME) of synaptic vesicles and synaptic transmission; acute haloperidol administration recovers Syt1 sorting and synaptic transmission deficits in STON2307Pro851Ala knockin mice. Co-immunoprecipitation; STON2307Pro851Ala knockin mouse electrophysiology; Syt1 sorting assay; haloperidol rescue experiment Science bulletin Medium 38402028
2024 Neutralization of highly conserved polybasic patches in either the C2A or C2B domain of SYT1 impairs both dense core vesicle (DCV) docking to the plasma membrane and efficient serotonin release; the same mutations result in larger fusion pores and faster serotonin release during individual fusion events, linking SYT1's polybasic regions to vesicle docking, fusion triggering, and fusion pore regulation. Site-directed mutagenesis of polybasic patches; DCV docking assay; single-vesicle serotonin release measurement in human neuroendocrine cell line bioRxivpreprint Medium bio_10.1101_2024.09.12.612660
2025 In bronchial epithelial cells, SYT1 localizes to late endo-lysosomes and MR1 vesicles; loss of Syt1 (and Syt7) results in enlarged MR1 vesicles and increased proximity of MR1 vesicles to Mtb-containing vacuoles, impairing MR1-mediated presentation of Mycobacterium tuberculosis antigens to MAIT cells. Immunofluorescence localization; Syt1/Syt7 loss-of-function in bronchial epithelial cells; MR1 vesicle morphology and MAIT cell activation assay bioRxivpreprint Medium bio_10.1101_2025.06.23.660389
2025 In human monocyte-derived macrophages treated with 4-HNE, SYT1 is strongly upregulated and localizes predominantly to the plasma membrane; SYT1 overexpression inhibits phagocytosis of pathogenic bacteria, revealing a non-neuronal role for SYT1 in suppressing macrophage phagocytic function. Transcriptomics; overexpression of fluorescent-reporter-tagged SYT1; phagocytosis functional assay in macrophages bioRxivpreprint Low bio_10.1101_2025.11.24.690103
2025 SNT-1 (C. elegans functional analog of Syt1) mediates fast evoked neurotransmitter release through C2B–SNARE complex interactions and polybasic motifs within its C2 domains; these interactions are required for both synchronous evoked and spontaneous release, with spontaneous release involving multiple SNARE-binding pathways beyond the primary C2B–SNARE interface. AlphaFold3 structural modeling; targeted mutagenesis; electrophysiology at C. elegans NMJ bioRxivpreprint Medium bio_10.1101_2025.09.30.679486

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell reports 300 24183667
2018 SYT1-associated neurodevelopmental disorder: a case series. Brain : a journal of neurology 112 30107533
2012 The oncogenic lung cancer fusion kinase CD74-ROS activates a novel invasiveness pathway through E-Syt1 phosphorylation. Cancer research 88 22659450
1996 Two synaptotagmin genes, Syt1 and Syt4, are differentially regulated in adult brain and during postnatal development following kainic acid-induced seizures. Brain research. Molecular brain research 54 8872307
2009 The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes. Proceedings of the National Academy of Sciences of the United States of America 52 19255425
2023 PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration. The Journal of cell biology 49 36821088
2010 A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level. BMC medical genetics 49 20222955
2019 E-syt1 Re-arranges STIM1 Clusters to Stabilize Ring-shaped ER-PM Contact Sites and Accelerate Ca2+ Store Replenishment. Scientific reports 45 30850711
2019 miRNA-34a suppresses colon carcinoma proliferation and induces cell apoptosis by targeting SYT1. International journal of clinical and experimental pathology 32 31934125
2017 Synaptotagmin2 (Syt2) Drives Fast Release Redundantly with Syt1 at the Output Synapses of Parvalbumin-Expressing Inhibitory Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 28363983
2023 Presynaptic targeting of botulinum neurotoxin type A requires a tripartite PSG-Syt1-SV2 plasma membrane nanocluster for synaptic vesicle entry. The EMBO journal 28 37226896
2022 Advanced Glycosylation End Products Induced Synaptic Deficits and Cognitive Decline Through ROS-JNK-p53/miR-34c/SYT1 Axis in Diabetic Encephalopathy. Journal of Alzheimer's disease : JAD 20 35404278
2021 LncRNA-MIAT regulates the growth of SHSY5Y cells by regulating the miR-34-5p-SYT1 axis and exerts a neuroprotective effect in a mouse model of Parkinson's disease. American journal of translational research 19 34650678
2014 Whole genome analyses of a well-differentiated liposarcoma reveals novel SYT1 and DDR2 rearrangements. PloS one 16 24505276
2022 SYT1-Associated Neurodevelopmental Disorder: A Narrative Review. Children (Basel, Switzerland) 13 36291375
2024 miRNA-363-3p Hinders Proliferation, Migration, Invasion and Autophagy of Thyroid Cancer Cells by Controlling SYT1 Transcription to affect NF-κB. Endocrine, metabolic & immune disorders drug targets 11 37150983
2024 SV2A controls the surface nanoclustering and endocytic recruitment of Syt1 during synaptic vesicle recycling. Journal of neurochemistry 11 39091022
2023 Early life stress enhances the susceptibility to depression and interferes with neuroplasticity in the hippocampus of adolescent mice via regulating miR-34c-5p/SYT1 axis. Journal of psychiatric research 11 38181539
2022 Altered cognition and anxiety in adolescent offspring whose mothers underwent different-pattern maternal sleep deprivation, and cognition link to hippocampal expressions of Bdnf and Syt-1. Frontiers in behavioral neuroscience 11 36570704
2020 Endosidin 2 accelerates PIN2 endocytosis and disturbs intracellular trafficking of PIN2, PIN3, and PIN4 but not of SYT1. PloS one 10 32790800
2023 MicroRNA-19a regulates milk fat metabolism by targeting SYT1 in bovine mammary epithelial cells. International journal of biological macromolecules 9 37769766
2025 NLRP6 deficiency enhances macrophage-mediated phagocytosis via E-Syt1 to inhibit hepatocellular carcinoma progression. Gut 7 40473401
2024 Correlation between evoked neurotransmitter release and adaptive functions in SYT1-associated neurodevelopmental disorder. EBioMedicine 7 39481209
2023 Mitochondrial membrane biogenesis: A new pathway for lipid transport mediated by PERK/E-Syt1 complex. The Journal of cell biology 6 36821089
2021 A genetic interaction of NRXN2 with GABRE, SYT1 and CASK in migraine patients: a case-control study. The journal of headache and pain 6 34126933
2025 Multiple cAMP/PKA complexes at the STIM1 ER/PM junction specified by E-Syt1 and E-Syt2 reciprocally gates ANO1 (TMEM16A) via Ca2. Nature communications 5 40204782
2023 E-Syt1 Regulates Neuronal Activity-Dependent Endoplasmic Reticulum-Plasma Membrane Junctions and Surface Expression of AMPA Receptors. Contact (Thousand Oaks (Ventura County, Calif.)) 5 37484831
2021 Identification and a phased pH control strategy of diosgenin bio-synthesized by an endogenous Bacillus licheniformis Syt1 derived from Dioscorea zingiberensis C. H. Wright. Applied microbiology and biotechnology 5 34841464
2019 The association between SYT1-rs2251214 and cocaine use disorder further supports its role in psychiatry. Progress in neuro-psychopharmacology & biological psychiatry 5 31059723
2024 STON2 variations are involved in synaptic dysfunction and schizophrenia-like behaviors by regulating Syt1 trafficking. Science bulletin 4 38402028
2024 c.1103T>C (p.Ile368Th) de novo Variant in Synaptotagmin 1 (SYT1) Gene is Pathogenic, Leading to an Ultra-Rare Neurodevelopmental Disorder: The Baker-Gordon Syndrome. International medical case reports journal 3 38283597
2023 Lethal variant in the C2A domain may cause severe SYT1-associated neurodevelopmental disorder in the newborns. Neurogenetics 3 37930470
2023 Expanding Phenotype of SYT1-Related Neurodevelopmental Disorder: Case Report and Literature Review. Molecular syndromology 3 38058756
2021 miR-128 regulates epilepsy sensitivity in mice by suppressing SNAP-25 and SYT1 expression in the hippocampus. Biochemical and biophysical research communications 3 33571908
2025 Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport. Nature cell biology 2 40437229
2024 Expanding the genetic and phenotypic spectrum of Baker-Gordon syndrome: a new de novo SYT1 variant. Journal of genetics 2 39049490
2024 Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function. Redox biology 2 39675068
2025 A Complex Chromosome Rearrangement Disrupting SYT1 Supports Haploinsufficiency as a Cause of Baker-Gordon Syndrome. Case reports in genetics 1 41438914
2019 Association between cognitive performance and SYT1-rs2251214 among women with cocaine use disorder. Journal of neural transmission (Vienna, Austria : 1996) 1 31562556
2026 E-Syt1 recruits PI4KA to endoplasmic reticulum-plasma membrane junctions to enhance PI4P synthesis. Science China. Life sciences 0 42258130

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