{"gene":"SYT7","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2025,"finding":"Alternative splicing of the SYT7 juxtamembrane linker acts as a molecular switch: the α and β isoforms undergo liquid-liquid phase separation to form condensates, while the γ isoform forms aggregates. MINFLUX super-resolution microscopy showed SYT7 clusters in the active zone. The three isoforms diverge in their ability to regulate paired-pulse facilitation and synaptic depression.","method":"Biochemical phase-separation assays, iGluSnFR imaging, MINFLUX super-resolution microscopy","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — multiple orthogonal methods (phase-separation assay, functional imaging, super-resolution microscopy) in a single preprint lab; not yet peer-reviewed or independently replicated","pmids":["bio_10.1101_2025.10.27.684894"],"is_preprint":true},{"year":2025,"finding":"In C. elegans, the SYT7 functional analog SNT-3 requires C2B–SNARE interactions and polybasic motifs within its C2 domains to drive slow evoked neurotransmitter release, paralleling the mechanism of the SYT1 analog SNT-1 for fast release. SNT-3 and SNT-1 show differential dependence on distinct regions of the C2B–SNARE interface, indicating divergent mechanistic strategies for fast vs. slow Ca2+-triggered release.","method":"Electrophysiology, targeted mutagenesis of conserved SNARE-binding residues, AlphaFold 3 structural modeling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — electrophysiology with mutagenesis in a single preprint; C. elegans ortholog findings; not independently replicated","pmids":["bio_10.1101_2025.09.30.679486"],"is_preprint":true},{"year":2025,"finding":"In bronchial epithelial cells, SYT7 (together with SYT1) localizes to late endo-lysosomes and MR1 vesicles. Loss of SYT1 and SYT7 results in enlarged MR1 vesicles and increased MR1 vesicles near Mycobacterium tuberculosis-containing vacuoles, impairing MR1-mediated antigen presentation and MAIT cell activation.","method":"Fluorescence localization/imaging, loss-of-function (knockdown), MAIT cell activation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — direct localization with functional consequence (antigen presentation assay), single preprint lab, no independent replication","pmids":["bio_10.1101_2025.06.23.660389"],"is_preprint":true},{"year":2024,"finding":"Selective knockout of Syt7 in dentate gyrus granule cells abolishes short-term presynaptic facilitation at mossy fiber–CA3 synapses without affecting basal synaptic properties or long-term potentiation. Loss of Syt7-dependent facilitation reduces co-activity of CA3 pyramidal cells in vivo and impairs spatial memory (pattern completion) in mice.","method":"Conditional knockout mice (DG-specific Syt7 KO), hippocampal slice electrophysiology, in vivo Ca2+ imaging, behavioral tasks","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal readouts (electrophysiology, in vivo imaging, behavior) in a single preprint; consistent with prior Syt7 facilitation literature","pmids":["bio_10.1101_2024.09.10.612312"],"is_preprint":true},{"year":2024,"finding":"Syt7 knockdown in layer 2/3 pyramidal neurons of rat prefrontal cortex abolishes short-term synaptic facilitation and slows the Ca2+-dependent refilling rate of readily releasable vesicles with high fusion probability, demonstrating that Syt7 mediates facilitation via Ca2+- and Syt7-dependent overfilling of release sites.","method":"Gene knockdown, patch-clamp electrophysiology, pharmacological dissection (PLC/DAG pathway), trace fear memory behavioral assay, c-Fos immunostaining","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal methods (electrophysiology, pharmacology, behavior, immunostaining), single preprint lab","pmids":["bio_10.1101_2024.09.10.612266"],"is_preprint":true},{"year":2025,"finding":"TDP-43 depletion in human stem cell-derived neurons induces cryptic splicing and downregulation of SYT7, contributing to impaired synaptic transmission. Antisense oligonucleotides targeting the SYT7 cryptic exon partially rescue this synaptic deficit; combined targeting of multiple cryptic exons (including SYT7) almost fully rescues the synaptic deficit caused by TDP-43 loss.","method":"TDP-43 knockdown in iPSC-derived neurons, RNA splicing analysis, antisense oligonucleotide rescue, electrophysiology/synaptic transmission assay, postmortem human brain validation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with ASO in human neurons plus postmortem validation, single preprint lab","pmids":["bio_10.1101_2025.08.28.672801"],"is_preprint":true},{"year":2023,"finding":"OGG1 (8-oxoguanine DNA glycosylase) transcriptionally regulates SYT7 expression in pancreatic β cells, and this regulation is suppressed by excessive iron. SYT7 overexpression rescues impaired insulin secretion caused by iron overload or Ogg1 knockout, placing SYT7 downstream of OGG1 in a pathway controlling insulin exocytosis.","method":"Iron overload mouse models, Ogg1-null mice, db/db mice, SYT7 overexpression rescue, glucose tolerance tests, insulin secretion assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via rescue experiment across multiple mouse models, single lab","pmids":["37209177"],"is_preprint":false},{"year":2023,"finding":"SYT7 increases exosome secretion from NSCLC cells by upregulating syntaxin-1a and syntaxin-3. SYT7-driven exosomes transfer CEP55 protein to endothelial cells, where CEP55 activates the mTOR signaling pathway, promoting angiogenesis, invasion, and metastasis.","method":"SYT7 overexpression/knockdown, exosome isolation and quantification, Western blot for syntaxins, co-culture with HUVECs, tube formation assay, mTOR pathway analysis, STAT1 inhibitor treatment, in vivo xenograft","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays (exosome quantification, co-culture, in vivo), single lab, mechanistic pathway partially inferred","pmids":["37774826"],"is_preprint":false},{"year":2022,"finding":"SYT7 interacts with BRCA1 (confirmed by Co-IP) and this interaction inhibits BRCA1-mediated ubiquitination of HMGB3, thereby stabilizing HMGB3 protein levels. HMGB3 knockdown rescues the pro-tumorigenic effects of SYT7 overexpression in thyroid cancer cells, placing HMGB3 downstream of SYT7.","method":"Co-immunoprecipitation, GeneChip/IPA pathway analysis, UbiBrowser database, HMGB3 knockdown rescue experiments, in vivo xenograft","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction plus genetic rescue across multiple cell lines; single lab","pmids":["35073278"],"is_preprint":false},{"year":2023,"finding":"SYT7 promotes CLL development by inhibiting SYVN1 (an E3 ubiquitin ligase)-mediated ubiquitination of KNTC1 (kinetochore protein), thereby stabilizing KNTC1. KNTC1 knockdown attenuates the pro-proliferative effects of SYT7 overexpression in CLL cells, placing KNTC1 downstream of SYT7.","method":"Co-immunoprecipitation, GeneChip analysis, KNTC1 knockdown rescue, in vitro proliferation/apoptosis assays, in vivo xenograft","journal":"Biomarker research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction plus genetic rescue; single lab","pmids":["37280656"],"is_preprint":false},{"year":2025,"finding":"SYT7 binds ALDH1A3 (confirmed by immunoprecipitation–mass spectrometry) and promotes its deubiquitination, reducing ALDH1A3 degradation. Stabilized ALDH1A3 activates STAT3 signaling and glycolysis in NPC cells; ALDH1A3 knockdown phenotypes are rescued by SYT7 overexpression.","method":"Whole-genome gene arrays, immunoprecipitation–mass spectrometry, ubiquitination assay, ALDH1A3 knockdown rescue, glycolysis assay, STAT3 pathway analysis, in vivo tumor growth","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — IP-MS interaction plus functional rescue with multiple readouts, single lab","pmids":["40346036"],"is_preprint":false},{"year":2024,"finding":"A G-quadruplex structure formed by the -187 to -172 bp sequence of the SYT7 promoter (parallel topology confirmed by circular dichroism; critical role of the ninth guanine shown by site mutation) regulates SYT7 transcription. Treatment with G-quadruplex ligands TMPyP4 and Pyridostatin reduced SYT7 expression and tumor cell proliferation.","method":"Circular dichroism spectroscopy, site-directed mutagenesis of G-quadruplex, G-quadruplex ligand treatment (TMPyP4, Pyridostatin), SYT7 expression and proliferation assays","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — in vitro structural assay plus mutagenesis plus functional validation, single lab","pmids":["39320967"],"is_preprint":false},{"year":2021,"finding":"ΔNp63α transcriptionally suppresses SYT7 expression in HNSCC cells. Double knockdown of ΔNp63α and SYT7 partially reverses ΔNp63α-induced phenotypes in vitro and in vivo, establishing SYT7 as a downstream effector of ΔNp63α in HNSCC progression.","method":"Whole-gene expression profile microarray, shRNA knockdown, rescue (double KD) experiments in vitro and in vivo (xenograft)","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transcriptomics plus genetic rescue in vitro and in vivo, single lab","pmids":["34930262"],"is_preprint":false},{"year":2024,"finding":"SYT7 knockdown in breast cancer cells reduces PI3K/AKT signaling (assessed by Western blot of pathway components), suppresses proliferation, and promotes apoptosis, placing SYT7 upstream of the PI3K/AKT pathway in breast cancer cells.","method":"shRNA knockdown, Western blot for PI3K/AKT components, CCK-8 proliferation assay, clone formation, flow cytometry apoptosis","journal":"Translational cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method for pathway placement (Western blot), no direct interaction or rescue experiment","pmids":["38988943"],"is_preprint":false}],"current_model":"SYT7 is a presynaptic calcium sensor that mediates short-term synaptic facilitation by promoting Ca2+-dependent vesicle replenishment and overfilling of readily releasable pools via C2B domain–SNARE interactions; its juxtamembrane linker undergoes alternative splicing to produce isoforms that differentially oligomerize (liquid-liquid phase separation vs. aggregation) and tune facilitation vs. depression; in non-neuronal contexts SYT7 regulates exocytosis/exosome secretion (upregulating syntaxin-1a/3), promotes protein stability via inhibition of ubiquitination (for HMGB3/BRCA1, KNTC1/SYVN1, ALDH1A3), activates downstream oncogenic pathways (PI3K/AKT, mTOR, STAT3), and is transcriptionally regulated by OGG1 and G-quadruplex structures in its promoter."},"narrative":{"mechanistic_narrative":"SYT7 is a Ca2+-sensing synaptotagmin that mediates short-term presynaptic facilitation by promoting Ca2+-dependent overfilling and refilling of readily releasable vesicle pools [PMID:bio_10.1101_2024.09.10.612312, PMID:bio_10.1101_2024.09.10.612266]. At mossy fiber–CA3 synapses, dentate gyrus-specific Syt7 knockout selectively abolishes short-term facilitation without altering basal release or LTP, and this loss degrades CA3 co-activity and spatial pattern-completion memory in vivo [PMID:bio_10.1101_2024.09.10.612312]; in prefrontal cortical neurons Syt7 knockdown likewise abolishes facilitation by slowing the Ca2+-dependent refilling of high-fusion-probability release sites [PMID:bio_10.1101_2024.09.10.612266]. Alternative splicing of the SYT7 juxtamembrane linker generates isoforms that differ in their biophysical behavior — α and β isoforms undergo liquid–liquid phase separation while the γ isoform aggregates — and these isoforms diverge in their capacity to tune facilitation versus depression, with SYT7 clustering resolved in the active zone by super-resolution imaging [PMID:bio_10.1101_2025.10.27.684894]. The slow-release mechanism depends on C2B–SNARE interactions and C2-domain polybasic motifs, as shown for the C. elegans analog SNT-3 [PMID:bio_10.1101_2025.09.30.679486]. SYT7 expression is set by transcriptional inputs including an OGG1-controlled program in pancreatic β cells, where SYT7 acts downstream of OGG1 to support insulin exocytosis [PMID:37209177], and a G-quadruplex element in its promoter [PMID:39320967]. Beyond neurons, SYT7 contributes to vesicular/endo-lysosomal trafficking — it localizes with SYT1 to late endo-lysosomes and MR1 vesicles where its loss impairs MR1 antigen presentation [PMID:bio_10.1101_2025.06.23.660389] — and in cancer it drives exosome secretion and stabilizes partner proteins by limiting their ubiquitination, including BRCA1-dependent HMGB3 stabilization in thyroid cancer [PMID:35073278], SYVN1-substrate KNTC1 in CLL [PMID:37280656], and ALDH1A3 in nasopharyngeal carcinoma [PMID:40346036].","teleology":[{"year":2021,"claim":"Established SYT7 as a transcriptionally regulated downstream effector in epithelial cancer, opening a non-neuronal functional axis.","evidence":"Expression microarray with shRNA double-knockdown rescue in HNSCC cells, in vitro and xenograft","pmids":["34930262"],"confidence":"Medium","gaps":["Does not define how SYT7 protein executes pro-tumor phenotype downstream","Single lab, single tumor type"]},{"year":2022,"claim":"Showed SYT7 stabilizes oncogenic substrates by interfering with ubiquitination, revealing a protein-stability mechanism distinct from its vesicle-fusion role.","evidence":"Co-IP of SYT7–BRCA1, ubiquitination assay, HMGB3 knockdown rescue across cell lines and xenograft (thyroid cancer)","pmids":["35073278"],"confidence":"Medium","gaps":["Co-IP without structural definition of binding interface","Mechanism of ubiquitination inhibition not resolved"]},{"year":2023,"claim":"Extended the ubiquitination-inhibition model to additional E3-ligase/substrate pairs and to exosome-mediated paracrine signaling, generalizing SYT7's oncogenic mechanisms.","evidence":"Co-IP/IP and rescue for KNTC1/SYVN1 (CLL); exosome quantification, syntaxin Western blots, HUVEC co-culture and mTOR analysis (NSCLC)","pmids":["37280656","37774826"],"confidence":"Medium","gaps":["Direct enzymatic deubiquitination activity of SYT7 not demonstrated","CEP55 exosome transfer mechanism partly inferred"]},{"year":2023,"claim":"Placed SYT7 downstream of OGG1 in controlling regulated exocytosis in a non-cancer secretory context (insulin release).","evidence":"Iron-overload, Ogg1-null and db/db mouse models with SYT7 overexpression rescue and insulin secretion assays","pmids":["37209177"],"confidence":"Medium","gaps":["Mechanism by which OGG1 drives SYT7 transcription not defined","Link to the synaptic facilitation mechanism unexplored"]},{"year":2024,"claim":"Demonstrated causally that SYT7 mediates short-term presynaptic facilitation via Ca2+-dependent overfilling/refilling of release sites and that this facilitation supports memory.","evidence":"DG-specific conditional KO and L2/3 cortical knockdown with slice electrophysiology, in vivo Ca2+ imaging, and behavioral assays","pmids":["bio_10.1101_2024.09.10.612312","bio_10.1101_2024.09.10.612266"],"confidence":"High","gaps":["Molecular structure of the overfilling mechanism not resolved","Preprint, single-lab readouts"]},{"year":2024,"claim":"Identified a promoter G-quadruplex as a cis-regulatory element controlling SYT7 transcription and a druggable handle for suppressing tumor SYT7 expression.","evidence":"Circular dichroism, G-quadruplex mutagenesis, and TMPyP4/Pyridostatin ligand treatment with expression/proliferation readouts","pmids":["39320967"],"confidence":"Medium","gaps":["Trans-acting factors binding the G-quadruplex not identified","Tissue specificity of regulation unclear"]},{"year":2025,"claim":"Resolved the molecular logic of SYT7 isoform diversity: juxtamembrane-linker splicing switches between phase-separating and aggregating forms that differentially tune facilitation versus depression.","evidence":"Phase-separation assays, iGluSnFR imaging, MINFLUX super-resolution localization of active-zone clusters","pmids":["bio_10.1101_2025.10.27.684894"],"confidence":"Medium","gaps":["Functional role of condensates in vivo not established","Preprint, not independently replicated"]},{"year":2025,"claim":"Defined the C2B–SNARE interface and C2-domain polybasic motifs as the structural basis for slow Ca2+-triggered release, distinguishing SYT7-type from SYT1-type mechanisms.","evidence":"Electrophysiology with targeted SNARE-binding mutagenesis and AlphaFold3 modeling of the C. elegans analog SNT-3","pmids":["bio_10.1101_2025.09.30.679486"],"confidence":"Medium","gaps":["Findings in C. elegans ortholog, not human SYT7","Direct structure of the human C2B–SNARE complex not determined"]},{"year":2025,"claim":"Connected SYT7 loss to disease-relevant synaptic dysfunction (TDP-43 cryptic splicing) and to endo-lysosomal antigen-presentation trafficking, broadening its trafficking roles.","evidence":"TDP-43 knockdown in iPSC neurons with ASO rescue and postmortem validation; SYT7/SYT1 localization and knockdown affecting MR1 vesicles and MAIT activation","pmids":["bio_10.1101_2025.08.28.672801","bio_10.1101_2025.06.23.660389"],"confidence":"Medium","gaps":["Whether SYT7 acts as a Ca2+ sensor at MR1 vesicles not tested","Preprints, single labs"]},{"year":null,"claim":"How SYT7's vesicle-fusion Ca2+-sensing activity mechanistically relates to its reported protein-stabilization and ubiquitination-inhibition functions in cancer remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model linking synaptic and oncogenic mechanisms","No direct demonstration that SYT7 possesses or recruits deubiquitinating activity","Human in vivo structural data on the C2B–SNARE interface lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[8,9,10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,7]}],"pathway":[],"complexes":[],"partners":["BRCA1","HMGB3","KNTC1","SYVN1","ALDH1A3","SYT1","STX1A","STX3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43581","full_name":"Synaptotagmin-7","aliases":["IPCA-7","Prostate cancer-associated protein 7","Synaptotagmin VII","SytVII"],"length_aa":403,"mass_kda":45.5,"function":"Ca(2+) sensor involved in Ca(2+)-dependent exocytosis of secretory and synaptic vesicles through Ca(2+) and phospholipid binding to the C2 domain (By similarity). Ca(2+) induces binding of the C2-domains to phospholipid membranes and to assembled SNARE-complexes; both actions contribute to triggering exocytosis (By similarity). SYT7 binds Ca(2+) with high affinity and slow kinetics compared to other synaptotagmins (By similarity). Involved in Ca(2+)-triggered lysosomal exocytosis, a major component of the plasma membrane repair (PubMed:11342594). Ca(2+)-regulated delivery of lysosomal membranes to the cell surface is also involved in the phagocytic uptake of particles by macrophages (By similarity). Ca(2+)-triggered lysosomal exocytosis also plays a role in bone remodeling by regulating secretory pathways in osteoclasts and osteoblasts (By similarity). In case of infection, involved in participates cell invasion by Trypanosoma cruzi via Ca(2+)-triggered lysosomal exocytosis (PubMed:11342594, PubMed:15811535). Involved in cholesterol transport from lysosome to peroxisome by promoting membrane contacts between lysosomes and peroxisomes: probably acts by promoting vesicle fusion by binding phosphatidylinositol-4,5-bisphosphate on peroxisomal membranes (By similarity). Acts as a key mediator of synaptic facilitation, a process also named short-term synaptic potentiation: synaptic facilitation takes place at synapses with a low initial release probability and is caused by influx of Ca(2+) into the axon terminal after spike generation, increasing the release probability of neurotransmitters (By similarity). Probably mediates synaptic facilitation by directly increasing the probability of release (By similarity). May also contribute to synaptic facilitation by regulating synaptic vesicle replenishment, a process required to ensure that synaptic vesicles are ready for the arrival of the next action potential: SYT7 is required for synaptic vesicle replenishment by acting as a sensor for Ca(2+) and by forming a complex with calmodulin (By similarity). Also acts as a regulator of Ca(2+)-dependent insulin and glucagon secretion in beta-cells (By similarity). Triggers exocytosis by promoting fusion pore opening and fusion pore expansion in chromaffin cells (By similarity). Also regulates the secretion of some non-synaptic secretory granules of specialized cells (By similarity)","subcellular_location":"Cell membrane; Presynaptic cell membrane; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Lysosome membrane; Cytoplasmic vesicle, phagosome membrane; Peroxisome membrane; Cytoplasmic vesicle, secretory vesicle membrane","url":"https://www.uniprot.org/uniprotkb/O43581/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYT7","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SYT7","total_profiled":1310},"omim":[{"mim_id":"616686","title":"SYNAPTOTAGMIN-BINDING CYTOPLASMIC RNA-INTERACTING PROTEIN; SYNCRIP","url":"https://www.omim.org/entry/616686"},{"mim_id":"610243","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 27; ZFYVE27","url":"https://www.omim.org/entry/610243"},{"mim_id":"607799","title":"ZDHHC PALMITOYLTRANSFERASE 17; ZDHHC17","url":"https://www.omim.org/entry/607799"},{"mim_id":"607182","title":"FYVE AND COILED-COIL DOMAIN CONTAINING 1; FYCO1","url":"https://www.omim.org/entry/607182"},{"mim_id":"604146","title":"SYNAPTOTAGMIN 7; SYT7","url":"https://www.omim.org/entry/604146"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":60.4},{"tissue":"liver","ntpm":79.3},{"tissue":"prostate","ntpm":47.8},{"tissue":"salivary gland","ntpm":53.7}],"url":"https://www.proteinatlas.org/search/SYT7"},"hgnc":{"alias_symbol":["IPCA-7","SYT-VII","MGC150517"],"prev_symbol":["PCANAP7"]},"alphafold":{"accession":"O43581","domains":[{"cath_id":"2.60.40.150","chopping":"139-257","consensus_level":"high","plddt":94.4156,"start":139,"end":257},{"cath_id":"2.60.40.150","chopping":"269-402","consensus_level":"high","plddt":94.906,"start":269,"end":402}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43581","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43581-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43581-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYT7","jax_strain_url":"https://www.jax.org/strain/search?query=SYT7"},"sequence":{"accession":"O43581","fasta_url":"https://rest.uniprot.org/uniprotkb/O43581.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43581/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43581"}},"corpus_meta":[{"pmid":"29858600","id":"PMC_29858600","title":"SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29858600","citation_count":58,"is_preprint":false},{"pmid":"37774826","id":"PMC_37774826","title":"SYT7 is a key player in increasing exosome secretion and promoting angiogenesis in non-small-cell lung cancer.","date":"2023","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/37774826","citation_count":25,"is_preprint":false},{"pmid":"28990113","id":"PMC_28990113","title":"Downregulation of SYT7 inhibits glioblastoma growth by promoting cellular apoptosis.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28990113","citation_count":17,"is_preprint":false},{"pmid":"35073278","id":"PMC_35073278","title":"SYT7 plays a role in promoting thyroid cancer by mediating HMGB3 ubiquitination.","date":"2022","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35073278","citation_count":12,"is_preprint":false},{"pmid":"37280656","id":"PMC_37280656","title":"SYT7 regulates the progression of chronic lymphocytic leukemia through interacting and regulating KNTC1.","date":"2023","source":"Biomarker research","url":"https://pubmed.ncbi.nlm.nih.gov/37280656","citation_count":10,"is_preprint":false},{"pmid":"34930262","id":"PMC_34930262","title":"SYT7 acts as an oncogene and a potential therapeutic target and was regulated by ΔNp63α in HNSCC.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/34930262","citation_count":10,"is_preprint":false},{"pmid":"36495510","id":"PMC_36495510","title":"Circ_0022340 promotes colorectal cancer progression via HNRNPC/EBF1/SYT7 or miR-382-5p/ELK1 axis.","date":"2022","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/36495510","citation_count":10,"is_preprint":false},{"pmid":"37209177","id":"PMC_37209177","title":"Excessive iron inhibits insulin secretion via perturbing transcriptional regulation of SYT7 by OGG1.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37209177","citation_count":10,"is_preprint":false},{"pmid":"38314285","id":"PMC_38314285","title":"SYT7 (synaptotagmin 7) promotes cervical squamous cell carcinoma.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38314285","citation_count":2,"is_preprint":false},{"pmid":"38988943","id":"PMC_38988943","title":"SYT7 promotes breast cancer cells growth through the PI3K/AKT pathway.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38988943","citation_count":1,"is_preprint":false},{"pmid":"39320967","id":"PMC_39320967","title":"G-Quadruplex-Mediated Transcriptional Regulation of SYT7: Implications for Tumor Progression and Therapeutic Strategies.","date":"2024","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39320967","citation_count":1,"is_preprint":false},{"pmid":"40346036","id":"PMC_40346036","title":"SYT7 accelerates nasopharyngeal carcinoma progression via ALDH1A3-mediated STAT3 signaling activation.","date":"2025","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/40346036","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.27.684894","title":"Alternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity","date":"2025-10-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.27.684894","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.30.679486","title":"Evolutionarily Conserved and Divergent Mechanisms of Dual Ca  <sup>2+</sup>  Sensors in Synaptic Vesicle Exocytosis","date":"2025-10-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.30.679486","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.23.660389","title":"Synaptotagmin 1 and Synaptotagmin 7 promote MR1-mediated presentation of  <i>Mycobacterium tuberculosis</i>  antigens","date":"2025-06-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.23.660389","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.28.672801","title":"Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction","date":"2025-09-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.28.672801","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.10.612312","title":"Abrogation of presynaptic facilitation at hippocampal mossy fiber synapses impacts neural ensemble activity and spatial memory","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.10.612312","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.10.612266","title":"Progressive overfilling of readily releasable pool underlies short-term facilitation at recurrent excitatory synapses in layer 2/3 of the rat prefrontal cortex","date":"2024-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.10.612266","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.30.656396","title":"Molecular subtyping based on hippocampal cryptic exon burden reveals proteome-wide changes associated with TDP-43 pathology across the spectrum of LATE and Alzheimer’s Disease","date":"2025-06-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.30.656396","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11904,"output_tokens":3766,"usd":0.046101,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11518,"output_tokens":3419,"usd":0.071532,"stage2_stop_reason":"end_turn"},"total_usd":0.117633,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"Alternative splicing of the SYT7 juxtamembrane linker acts as a molecular switch: the α and β isoforms undergo liquid-liquid phase separation to form condensates, while the γ isoform forms aggregates. MINFLUX super-resolution microscopy showed SYT7 clusters in the active zone. The three isoforms diverge in their ability to regulate paired-pulse facilitation and synaptic depression.\",\n      \"method\": \"Biochemical phase-separation assays, iGluSnFR imaging, MINFLUX super-resolution microscopy\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — multiple orthogonal methods (phase-separation assay, functional imaging, super-resolution microscopy) in a single preprint lab; not yet peer-reviewed or independently replicated\",\n      \"pmids\": [\"bio_10.1101_2025.10.27.684894\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, the SYT7 functional analog SNT-3 requires C2B–SNARE interactions and polybasic motifs within its C2 domains to drive slow evoked neurotransmitter release, paralleling the mechanism of the SYT1 analog SNT-1 for fast release. SNT-3 and SNT-1 show differential dependence on distinct regions of the C2B–SNARE interface, indicating divergent mechanistic strategies for fast vs. slow Ca2+-triggered release.\",\n      \"method\": \"Electrophysiology, targeted mutagenesis of conserved SNARE-binding residues, AlphaFold 3 structural modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — electrophysiology with mutagenesis in a single preprint; C. elegans ortholog findings; not independently replicated\",\n      \"pmids\": [\"bio_10.1101_2025.09.30.679486\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In bronchial epithelial cells, SYT7 (together with SYT1) localizes to late endo-lysosomes and MR1 vesicles. Loss of SYT1 and SYT7 results in enlarged MR1 vesicles and increased MR1 vesicles near Mycobacterium tuberculosis-containing vacuoles, impairing MR1-mediated antigen presentation and MAIT cell activation.\",\n      \"method\": \"Fluorescence localization/imaging, loss-of-function (knockdown), MAIT cell activation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — direct localization with functional consequence (antigen presentation assay), single preprint lab, no independent replication\",\n      \"pmids\": [\"bio_10.1101_2025.06.23.660389\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Selective knockout of Syt7 in dentate gyrus granule cells abolishes short-term presynaptic facilitation at mossy fiber–CA3 synapses without affecting basal synaptic properties or long-term potentiation. Loss of Syt7-dependent facilitation reduces co-activity of CA3 pyramidal cells in vivo and impairs spatial memory (pattern completion) in mice.\",\n      \"method\": \"Conditional knockout mice (DG-specific Syt7 KO), hippocampal slice electrophysiology, in vivo Ca2+ imaging, behavioral tasks\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal readouts (electrophysiology, in vivo imaging, behavior) in a single preprint; consistent with prior Syt7 facilitation literature\",\n      \"pmids\": [\"bio_10.1101_2024.09.10.612312\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Syt7 knockdown in layer 2/3 pyramidal neurons of rat prefrontal cortex abolishes short-term synaptic facilitation and slows the Ca2+-dependent refilling rate of readily releasable vesicles with high fusion probability, demonstrating that Syt7 mediates facilitation via Ca2+- and Syt7-dependent overfilling of release sites.\",\n      \"method\": \"Gene knockdown, patch-clamp electrophysiology, pharmacological dissection (PLC/DAG pathway), trace fear memory behavioral assay, c-Fos immunostaining\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal methods (electrophysiology, pharmacology, behavior, immunostaining), single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.10.612266\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TDP-43 depletion in human stem cell-derived neurons induces cryptic splicing and downregulation of SYT7, contributing to impaired synaptic transmission. Antisense oligonucleotides targeting the SYT7 cryptic exon partially rescue this synaptic deficit; combined targeting of multiple cryptic exons (including SYT7) almost fully rescues the synaptic deficit caused by TDP-43 loss.\",\n      \"method\": \"TDP-43 knockdown in iPSC-derived neurons, RNA splicing analysis, antisense oligonucleotide rescue, electrophysiology/synaptic transmission assay, postmortem human brain validation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with ASO in human neurons plus postmortem validation, single preprint lab\",\n      \"pmids\": [\"bio_10.1101_2025.08.28.672801\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OGG1 (8-oxoguanine DNA glycosylase) transcriptionally regulates SYT7 expression in pancreatic β cells, and this regulation is suppressed by excessive iron. SYT7 overexpression rescues impaired insulin secretion caused by iron overload or Ogg1 knockout, placing SYT7 downstream of OGG1 in a pathway controlling insulin exocytosis.\",\n      \"method\": \"Iron overload mouse models, Ogg1-null mice, db/db mice, SYT7 overexpression rescue, glucose tolerance tests, insulin secretion assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via rescue experiment across multiple mouse models, single lab\",\n      \"pmids\": [\"37209177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SYT7 increases exosome secretion from NSCLC cells by upregulating syntaxin-1a and syntaxin-3. SYT7-driven exosomes transfer CEP55 protein to endothelial cells, where CEP55 activates the mTOR signaling pathway, promoting angiogenesis, invasion, and metastasis.\",\n      \"method\": \"SYT7 overexpression/knockdown, exosome isolation and quantification, Western blot for syntaxins, co-culture with HUVECs, tube formation assay, mTOR pathway analysis, STAT1 inhibitor treatment, in vivo xenograft\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays (exosome quantification, co-culture, in vivo), single lab, mechanistic pathway partially inferred\",\n      \"pmids\": [\"37774826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SYT7 interacts with BRCA1 (confirmed by Co-IP) and this interaction inhibits BRCA1-mediated ubiquitination of HMGB3, thereby stabilizing HMGB3 protein levels. HMGB3 knockdown rescues the pro-tumorigenic effects of SYT7 overexpression in thyroid cancer cells, placing HMGB3 downstream of SYT7.\",\n      \"method\": \"Co-immunoprecipitation, GeneChip/IPA pathway analysis, UbiBrowser database, HMGB3 knockdown rescue experiments, in vivo xenograft\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction plus genetic rescue across multiple cell lines; single lab\",\n      \"pmids\": [\"35073278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SYT7 promotes CLL development by inhibiting SYVN1 (an E3 ubiquitin ligase)-mediated ubiquitination of KNTC1 (kinetochore protein), thereby stabilizing KNTC1. KNTC1 knockdown attenuates the pro-proliferative effects of SYT7 overexpression in CLL cells, placing KNTC1 downstream of SYT7.\",\n      \"method\": \"Co-immunoprecipitation, GeneChip analysis, KNTC1 knockdown rescue, in vitro proliferation/apoptosis assays, in vivo xenograft\",\n      \"journal\": \"Biomarker research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction plus genetic rescue; single lab\",\n      \"pmids\": [\"37280656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SYT7 binds ALDH1A3 (confirmed by immunoprecipitation–mass spectrometry) and promotes its deubiquitination, reducing ALDH1A3 degradation. Stabilized ALDH1A3 activates STAT3 signaling and glycolysis in NPC cells; ALDH1A3 knockdown phenotypes are rescued by SYT7 overexpression.\",\n      \"method\": \"Whole-genome gene arrays, immunoprecipitation–mass spectrometry, ubiquitination assay, ALDH1A3 knockdown rescue, glycolysis assay, STAT3 pathway analysis, in vivo tumor growth\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — IP-MS interaction plus functional rescue with multiple readouts, single lab\",\n      \"pmids\": [\"40346036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A G-quadruplex structure formed by the -187 to -172 bp sequence of the SYT7 promoter (parallel topology confirmed by circular dichroism; critical role of the ninth guanine shown by site mutation) regulates SYT7 transcription. Treatment with G-quadruplex ligands TMPyP4 and Pyridostatin reduced SYT7 expression and tumor cell proliferation.\",\n      \"method\": \"Circular dichroism spectroscopy, site-directed mutagenesis of G-quadruplex, G-quadruplex ligand treatment (TMPyP4, Pyridostatin), SYT7 expression and proliferation assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — in vitro structural assay plus mutagenesis plus functional validation, single lab\",\n      \"pmids\": [\"39320967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ΔNp63α transcriptionally suppresses SYT7 expression in HNSCC cells. Double knockdown of ΔNp63α and SYT7 partially reverses ΔNp63α-induced phenotypes in vitro and in vivo, establishing SYT7 as a downstream effector of ΔNp63α in HNSCC progression.\",\n      \"method\": \"Whole-gene expression profile microarray, shRNA knockdown, rescue (double KD) experiments in vitro and in vivo (xenograft)\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transcriptomics plus genetic rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"34930262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SYT7 knockdown in breast cancer cells reduces PI3K/AKT signaling (assessed by Western blot of pathway components), suppresses proliferation, and promotes apoptosis, placing SYT7 upstream of the PI3K/AKT pathway in breast cancer cells.\",\n      \"method\": \"shRNA knockdown, Western blot for PI3K/AKT components, CCK-8 proliferation assay, clone formation, flow cytometry apoptosis\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method for pathway placement (Western blot), no direct interaction or rescue experiment\",\n      \"pmids\": [\"38988943\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYT7 is a presynaptic calcium sensor that mediates short-term synaptic facilitation by promoting Ca2+-dependent vesicle replenishment and overfilling of readily releasable pools via C2B domain–SNARE interactions; its juxtamembrane linker undergoes alternative splicing to produce isoforms that differentially oligomerize (liquid-liquid phase separation vs. aggregation) and tune facilitation vs. depression; in non-neuronal contexts SYT7 regulates exocytosis/exosome secretion (upregulating syntaxin-1a/3), promotes protein stability via inhibition of ubiquitination (for HMGB3/BRCA1, KNTC1/SYVN1, ALDH1A3), activates downstream oncogenic pathways (PI3K/AKT, mTOR, STAT3), and is transcriptionally regulated by OGG1 and G-quadruplex structures in its promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SYT7 is a Ca2+-sensing synaptotagmin that mediates short-term presynaptic facilitation by promoting Ca2+-dependent overfilling and refilling of readily releasable vesicle pools [#3, #4]. At mossy fiber–CA3 synapses, dentate gyrus-specific Syt7 knockout selectively abolishes short-term facilitation without altering basal release or LTP, and this loss degrades CA3 co-activity and spatial pattern-completion memory in vivo [#3]; in prefrontal cortical neurons Syt7 knockdown likewise abolishes facilitation by slowing the Ca2+-dependent refilling of high-fusion-probability release sites [#4]. Alternative splicing of the SYT7 juxtamembrane linker generates isoforms that differ in their biophysical behavior — α and β isoforms undergo liquid–liquid phase separation while the γ isoform aggregates — and these isoforms diverge in their capacity to tune facilitation versus depression, with SYT7 clustering resolved in the active zone by super-resolution imaging [#0]. The slow-release mechanism depends on C2B–SNARE interactions and C2-domain polybasic motifs, as shown for the C. elegans analog SNT-3 [#1]. SYT7 expression is set by transcriptional inputs including an OGG1-controlled program in pancreatic β cells, where SYT7 acts downstream of OGG1 to support insulin exocytosis [#6], and a G-quadruplex element in its promoter [#11]. Beyond neurons, SYT7 contributes to vesicular/endo-lysosomal trafficking — it localizes with SYT1 to late endo-lysosomes and MR1 vesicles where its loss impairs MR1 antigen presentation [#2] — and in cancer it drives exosome secretion and stabilizes partner proteins by limiting their ubiquitination, including BRCA1-dependent HMGB3 stabilization in thyroid cancer [#8], SYVN1-substrate KNTC1 in CLL [#9], and ALDH1A3 in nasopharyngeal carcinoma [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established SYT7 as a transcriptionally regulated downstream effector in epithelial cancer, opening a non-neuronal functional axis.\",\n      \"evidence\": \"Expression microarray with shRNA double-knockdown rescue in HNSCC cells, in vitro and xenograft\",\n      \"pmids\": [\"34930262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define how SYT7 protein executes pro-tumor phenotype downstream\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SYT7 stabilizes oncogenic substrates by interfering with ubiquitination, revealing a protein-stability mechanism distinct from its vesicle-fusion role.\",\n      \"evidence\": \"Co-IP of SYT7–BRCA1, ubiquitination assay, HMGB3 knockdown rescue across cell lines and xenograft (thyroid cancer)\",\n      \"pmids\": [\"35073278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP without structural definition of binding interface\", \"Mechanism of ubiquitination inhibition not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the ubiquitination-inhibition model to additional E3-ligase/substrate pairs and to exosome-mediated paracrine signaling, generalizing SYT7's oncogenic mechanisms.\",\n      \"evidence\": \"Co-IP/IP and rescue for KNTC1/SYVN1 (CLL); exosome quantification, syntaxin Western blots, HUVEC co-culture and mTOR analysis (NSCLC)\",\n      \"pmids\": [\"37280656\", \"37774826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct enzymatic deubiquitination activity of SYT7 not demonstrated\", \"CEP55 exosome transfer mechanism partly inferred\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SYT7 downstream of OGG1 in controlling regulated exocytosis in a non-cancer secretory context (insulin release).\",\n      \"evidence\": \"Iron-overload, Ogg1-null and db/db mouse models with SYT7 overexpression rescue and insulin secretion assays\",\n      \"pmids\": [\"37209177\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which OGG1 drives SYT7 transcription not defined\", \"Link to the synaptic facilitation mechanism unexplored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated causally that SYT7 mediates short-term presynaptic facilitation via Ca2+-dependent overfilling/refilling of release sites and that this facilitation supports memory.\",\n      \"evidence\": \"DG-specific conditional KO and L2/3 cortical knockdown with slice electrophysiology, in vivo Ca2+ imaging, and behavioral assays\",\n      \"pmids\": [\"bio_10.1101_2024.09.10.612312\", \"bio_10.1101_2024.09.10.612266\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular structure of the overfilling mechanism not resolved\", \"Preprint, single-lab readouts\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a promoter G-quadruplex as a cis-regulatory element controlling SYT7 transcription and a druggable handle for suppressing tumor SYT7 expression.\",\n      \"evidence\": \"Circular dichroism, G-quadruplex mutagenesis, and TMPyP4/Pyridostatin ligand treatment with expression/proliferation readouts\",\n      \"pmids\": [\"39320967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting factors binding the G-quadruplex not identified\", \"Tissue specificity of regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the molecular logic of SYT7 isoform diversity: juxtamembrane-linker splicing switches between phase-separating and aggregating forms that differentially tune facilitation versus depression.\",\n      \"evidence\": \"Phase-separation assays, iGluSnFR imaging, MINFLUX super-resolution localization of active-zone clusters\",\n      \"pmids\": [\"bio_10.1101_2025.10.27.684894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of condensates in vivo not established\", \"Preprint, not independently replicated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the C2B–SNARE interface and C2-domain polybasic motifs as the structural basis for slow Ca2+-triggered release, distinguishing SYT7-type from SYT1-type mechanisms.\",\n      \"evidence\": \"Electrophysiology with targeted SNARE-binding mutagenesis and AlphaFold3 modeling of the C. elegans analog SNT-3\",\n      \"pmids\": [\"bio_10.1101_2025.09.30.679486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Findings in C. elegans ortholog, not human SYT7\", \"Direct structure of the human C2B–SNARE complex not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SYT7 loss to disease-relevant synaptic dysfunction (TDP-43 cryptic splicing) and to endo-lysosomal antigen-presentation trafficking, broadening its trafficking roles.\",\n      \"evidence\": \"TDP-43 knockdown in iPSC neurons with ASO rescue and postmortem validation; SYT7/SYT1 localization and knockdown affecting MR1 vesicles and MAIT activation\",\n      \"pmids\": [\"bio_10.1101_2025.08.28.672801\", \"bio_10.1101_2025.06.23.660389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SYT7 acts as a Ca2+ sensor at MR1 vesicles not tested\", \"Preprints, single labs\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SYT7's vesicle-fusion Ca2+-sensing activity mechanistically relates to its reported protein-stabilization and ubiquitination-inhibition functions in cancer remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical model linking synaptic and oncogenic mechanisms\", \"No direct demonstration that SYT7 possesses or recruits deubiquitinating activity\", \"Human in vivo structural data on the C2B–SNARE interface lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [8, 9, 10]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"BRCA1\", \"HMGB3\", \"KNTC1\", \"SYVN1\", \"ALDH1A3\", \"SYT1\", \"STX1A\", \"STX3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}