{"gene":"SYT6","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":1995,"finding":"Synaptotagmin VI (Syt6) shares the common synaptotagmin domain architecture (single transmembrane region + two C2 domains). The first C2 domain of Syt VI does NOT bind phospholipids in a Ca2+-dependent manner (unlike Syt I, II, III, V, VII). All Syt isoforms tested, including Syt VI, interact with clathrin-AP2 (Kd = 0.1–1.0 nM) and with neural and non-neural syntaxins via their cytoplasmic C2 domain region.","method":"In vitro binding assays, Ca2+-dependent phospholipid binding assays, clathrin-AP2 pull-down, syntaxin interaction assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical assays with multiple isoforms compared; foundational paper >550 citations","pmids":["7791877"],"is_preprint":false},{"year":1996,"finding":"The C-terminus of Syt6 (synaptotagmin 6) interacts with neurexins in a calcium-independent manner, mediated by two mirror-image sequence motifs (Leu-X-His-Trp and Trp-His-X-Leu) in the C-terminal 34 amino acids. The same C-terminal domain also mediates calcium-dependent enrichment of calmodulin via the first of these motifs. Deletion or substitution of residues in these motifs greatly reduces neurexin binding.","method":"Affinity purification from solubilized brain membranes, recombinant protein binding assays, site-directed mutagenesis, 125I-calmodulin binding","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution with mutagenesis identifying specific residues; multiple binding partners tested","pmids":["8901523"],"is_preprint":false},{"year":1999,"finding":"Synaptotagmin VI (along with Syt III, V, and X) forms beta-mercaptoethanol-sensitive homodimers and heterodimers via a conserved N-terminal cysteine motif (three cysteines at positions ~10, 21, and 33). Site-directed mutagenesis of the first cysteine residue abolishes stable homodimer formation of Syt VI and heterodimer formation between Syt VI and Syt III, V, or X.","method":"Co-immunoprecipitation, site-directed mutagenesis, reducing agent sensitivity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis combined with co-IP clearly identifies specific cysteine residues; multiple isoforms tested","pmids":["10531343"],"is_preprint":false},{"year":2001,"finding":"Synaptotagmin VI is localized to the outer acrosomal membrane of human sperm. A specific anti-Syt VI antibody and a recombinant GST fusion protein containing the C2A and C2B domains of Syt VI both abrogated calcium-triggered acrosomal exocytosis in permeabilized spermatozoa, demonstrating that Syt VI is required for this secretory process. Syt VI is also necessary for Rab3A-promoted acrosomal exocytosis at low calcium concentrations. Phorbol ester-dependent phosphorylation of the C2A–C2B fusion protein abolished its inhibitory effect on exocytosis.","method":"Western blot, immunocytochemistry (optical and electron microscopy), function-blocking antibody assays in permeabilized sperm, recombinant protein inhibition assays, in vitro phosphorylation","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization + antibody blocking + recombinant domain inhibition + phosphorylation rescue) in single study","pmids":["11437455"],"is_preprint":false},{"year":2001,"finding":"Genomic analysis identified human homologues for all known rodent synaptotagmin genes, establishing the full genomic structure of the synaptotagmin family. Comparison of genomic structures clarified the phylogeny of different subgroups, including Syt6, and revealed alternative splicing possibilities.","method":"TBLASTn genomic database searches, comparative genomic structure analysis","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 4 — computational/comparative genomics only, no direct functional experiment","pmids":["11543631"],"is_preprint":false},{"year":2005,"finding":"Protein kinase C betaII (PKCbetaII) phosphorylates Syt VI at Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain, and at Thr284 in the polybasic region (KCKLQTR) of the C2A domain. PKC-mediated phosphorylation of either C2 domain abolishes their inhibitory effect on acrosomal exocytosis in permeabilized spermatozoa. An antibody recognizing the phosphorylated C2B polybasic region detected endogenous phosphorylated Syt VI in the sperm acrosomal region, and immunolabeling decreased upon sperm stimulation, indicating dephosphorylation occurs during exocytosis.","method":"Site-directed mutagenesis, in vitro phosphorylation with purified PKCbetaII, function-blocking assays in permeabilized sperm, phospho-specific antibody immunolabeling","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 — site-directed mutagenesis identifying specific phosphorylation sites combined with functional exocytosis assays and endogenous protein detection","pmids":["16111671"],"is_preprint":false},{"year":2010,"finding":"Calcineurin (a calcium-dependent phosphatase) dephosphorylates Syt VI at the polybasic region of its C2B domain during the early stages of human sperm acrosomal exocytosis. This dephosphorylation is required for progression of exocytosis: calcineurin inhibition (cyclosporin A) blocked exocytosis, and an inhibitor-insensitive catalytically active calcineurin domain rescued it. Premature calcineurin-driven dephosphorylation before stimulation inhibited exocytosis, an effect rescued by a phosphomimetic Syt VI C2B-T418E/T419E mutant, demonstrating that temporally regulated dephosphorylation of Syt VI is essential.","method":"Calcineurin inhibitor (cyclosporin A) functional assays in permeabilized sperm, recombinant active calcineurin domain rescue, in vitro dephosphorylation of recombinant Syt VI C2B, phosphomimetic mutant rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal approaches including enzyme inhibition, active domain rescue, substrate mutagenesis, and phosphomimetic rescue","pmids":["20551332"],"is_preprint":false},{"year":2012,"finding":"Following ischemic insult, the transcriptional repressor REST (RE-1 silencing transcription factor) binds the syt6 gene promoter among a subset of target genes in hippocampal neurons. REST assembles a repressor complex containing CoREST, mSin3A, histone deacetylases 1 and 2, G9a histone methyltransferase, and MeCP2 at the syt6 promoter, orchestrating epigenetic silencing and reducing Syt6 mRNA and protein levels. RNAi-mediated depletion of REST prevented these epigenetic modifications and restored syt6 expression.","method":"ChIP (chromatin immunoprecipitation), RNAi knockdown in vivo, mRNA/protein quantification, in vivo hippocampal injection of dominant-negative REST","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP + RNAi rescue in vivo; Syt6 is one of ~8 genes examined, not the primary focus","pmids":["22371606"],"is_preprint":false},{"year":2015,"finding":"Among eight synaptotagmin isoforms examined, only Syt6 knockdown impaired activity-induced release of endocytosed (exogenous) BDNF-quantum dot conjugates from postsynaptic dendrites of cultured hippocampal neurons. Repetitive neuronal spiking triggered BDNF-QD release preferentially at postsynaptic sites in a glutamate receptor-dependent manner, and this required Syt6 (and complexin 1/2). In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6, indicating Syt6 specifically regulates exocytic release of endosomal (recycled) BDNF from dendrites.","method":"shRNA knockdown of individual Syt isoforms, quantum dot-tagged BDNF live imaging, activity-dependent secretion assays in cultured hippocampal neurons, glutamate receptor pharmacology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — selective isoform knockdown screen across 8 Syts combined with live imaging; isoform specificity rigorously demonstrated","pmids":["26216953"],"is_preprint":false},{"year":2021,"finding":"Syt6-Cre transgenic mice express Cre recombinase (and thus mark Syt6-expressing cells) predominantly in layer 6 corticothalamic neurons (CTn) and to a lesser extent layer 5 CTn in prefrontal, motor, cingulate, and retrosplenial cortices. Cortical expression begins embryonically and reaches the adult pattern by postnatal day 15. Optogenetic stimulation of Syt6-Cre+ neurons in prefrontal cortex induced oscillatory local field potential activity resembling cortical downstates observed during slow-wave sleep or quiet waking.","method":"Cre-reporter lineage tracing, immunohistochemistry, axon varicosity quantification, in vivo optogenetic stimulation with local field potential recording","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by reporter expression with functional consequence demonstrated by optogenetic stimulation","pmids":["34617601"],"is_preprint":false},{"year":2024,"finding":"Quantitative proteomic analysis of MPTP-induced Parkinson's disease mouse brain identified Syt6 as a hub node protein associated with regulatory T-cell (Treg) networks and rTMS treatment response. Virus-mediated RNA interference of Syt6 in MPTP mice was used to validate its functional role: Syt6 knockdown affected the therapeutic outcomes of rTMS on motor function and Treg modulation.","method":"Quantitative proteomics (label-free), virus-mediated RNAi in vivo, motor behavior assessment, flow cytometry of Tregs","journal":"Molecular neurodegeneration","confidence":"Low","confidence_rationale":"Tier 3 — proteomics identification + in vivo RNAi with behavioral readout, but molecular mechanism downstream of Syt6 not defined","pmids":["39456006"],"is_preprint":false}],"current_model":"Synaptotagmin 6 (SYT6) is a membrane protein with two C2 domains that lacks Ca2+-dependent phospholipid binding through its C2A domain but interacts with clathrin-AP2, syntaxins, and neurexins (via conserved C-terminal motifs) and calmodulin (Ca2+-dependently); it forms disulfide-linked homodimers and heterodimers with Syt III/V/X via N-terminal cysteine residues; in human sperm it localizes to the outer acrosomal membrane and is an essential component of the Ca2+-triggered acrosomal exocytosis machinery, regulated by PKCbetaII-mediated phosphorylation of conserved threonines in the C2A and C2B polybasic regions and by calcineurin-mediated dephosphorylation at the onset of exocytosis; in neurons it is expressed in layer 6 corticothalamic neurons and selectively mediates activity-dependent release of endosomal (recycled) BDNF from postsynaptic dendrites in a complexin-dependent manner; and its gene is subject to REST-dependent epigenetic silencing following ischemic insult."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing the biochemical identity of SYT6 resolved whether all synaptotagmin isoforms share the canonical Ca²⁺-dependent phospholipid-binding activity: SYT6's C2A domain does not bind phospholipids in a Ca²⁺-dependent manner, yet the protein retains high-affinity interactions with clathrin-AP2 and syntaxins, suggesting a specialized regulatory role.","evidence":"In vitro Ca²⁺-dependent phospholipid binding assays and pull-down assays comparing multiple Syt isoforms","pmids":["7791877"],"confidence":"High","gaps":["No structure of the SYT6 C2A domain explaining its divergent lipid-binding properties","Functional consequence of the AP2/syntaxin interactions for SYT6 specifically was not tested in cells"]},{"year":1996,"claim":"Identification of neurexin and calmodulin as C-terminal binding partners, mediated by mirror-image LXHW/WHXL motifs, revealed a molecular interface coupling SYT6 to synaptic cell-adhesion molecules and Ca²⁺/calmodulin signaling.","evidence":"Affinity purification from brain membranes, recombinant binding assays, and site-directed mutagenesis of C-terminal motifs","pmids":["8901523"],"confidence":"High","gaps":["Physiological relevance of the SYT6–neurexin interaction in intact synapses not demonstrated","Whether calmodulin binding modulates SYT6 exocytic function remains untested"]},{"year":1999,"claim":"Discovery that SYT6 forms disulfide-linked homodimers and heterodimers (with SYT3, SYT5, SYT10) via conserved N-terminal cysteines established a quaternary structural principle for the Syt family and raised the possibility that heteromeric complexes diversify exocytic regulation.","evidence":"Co-immunoprecipitation with reducing-agent sensitivity and cysteine mutagenesis","pmids":["10531343"],"confidence":"High","gaps":["Whether heterodimerization occurs in vivo in native tissues is unresolved","Functional consequence of dimerization for exocytosis not tested"]},{"year":2001,"claim":"Localization of SYT6 to the outer acrosomal membrane and demonstration that anti-SYT6 antibodies and recombinant C2 domains block Ca²⁺-triggered acrosomal exocytosis established the first cellular function for SYT6 as an essential exocytic calcium sensor in sperm.","evidence":"Immunocytochemistry, function-blocking antibody and recombinant-domain inhibition assays in permeabilized human spermatozoa","pmids":["11437455"],"confidence":"High","gaps":["Genetic loss-of-function confirmation (knockout) not available","SNARE complex partners at the acrosomal membrane not defined"]},{"year":2005,"claim":"Identification of PKCβII as the kinase that phosphorylates specific threonines in the C2A and C2B polybasic regions of SYT6 explained how phosphorylation relieves the inhibitory effect of C2 domains on exocytosis and implicated a phosphorylation-dependent priming mechanism.","evidence":"In vitro phosphorylation with purified PKCβII, site-directed mutagenesis (Thr284, Thr418/419), functional exocytosis assays in permeabilized sperm, phospho-specific antibody detection","pmids":["16111671"],"confidence":"High","gaps":["Crystal structure of phosphorylated versus unphosphorylated C2 domains not determined","Whether other kinases contribute in vivo unknown"]},{"year":2010,"claim":"Demonstrating that calcineurin-mediated dephosphorylation of SYT6 C2B polybasic threonines is temporally required at the onset of exocytosis completed a phosphorylation–dephosphorylation cycle model in which PKCβII primes and calcineurin activates SYT6-dependent membrane fusion.","evidence":"Cyclosporin A inhibition, catalytically active calcineurin rescue, in vitro dephosphorylation, and phosphomimetic T418E/T419E mutant rescue in permeabilized sperm","pmids":["20551332"],"confidence":"High","gaps":["Whether this phospho-cycle operates in neuronal exocytosis is unknown","Direct structural basis for how dephosphorylation enables membrane fusion not established"]},{"year":2012,"claim":"Showing that REST recruits a repressor complex (CoREST, mSin3A, HDAC1/2, G9a, MeCP2) to the SYT6 promoter after ischemia, silencing its expression, linked SYT6 to epigenetic regulation in neuronal injury, though SYT6 was one of several REST targets studied.","evidence":"ChIP and in vivo RNAi of REST in hippocampal neurons following ischemia","pmids":["22371606"],"confidence":"Medium","gaps":["Functional consequence of SYT6 downregulation specifically (vs. other REST targets) for ischemic pathology not isolated","Whether REST regulation of SYT6 occurs under non-pathological conditions not tested"]},{"year":2015,"claim":"A selective isoform-specific knockdown screen revealed that SYT6 — uniquely among eight synaptotagmins — is required for activity-dependent postsynaptic release of endosomal (recycled) BDNF from hippocampal dendrites, establishing a neuronal exocytic function distinct from presynaptic vesicle fusion.","evidence":"shRNA knockdown of individual Syt isoforms combined with quantum-dot-tagged BDNF live imaging and pharmacological dissection in cultured hippocampal neurons","pmids":["26216953"],"confidence":"High","gaps":["In vivo confirmation of dendritic BDNF release dependence on SYT6 not yet reported","SNARE partners mediating the SYT6-dependent dendritic exocytic step are undefined","Mechanism by which SYT6 distinguishes endosomal versus de novo BDNF vesicles is unknown"]},{"year":2021,"claim":"Lineage tracing with Syt6-Cre mice localized SYT6 expression predominantly to layer 6 corticothalamic neurons, and optogenetic activation of these neurons evoked cortical oscillations resembling slow-wave downstates, placing SYT6-expressing circuits in corticothalamic feedback control.","evidence":"Cre-reporter lineage tracing, immunohistochemistry, and in vivo optogenetic stimulation with LFP recording in prefrontal cortex","pmids":["34617601"],"confidence":"Medium","gaps":["Whether SYT6 protein function (vs. merely expression) is required for corticothalamic signaling not tested","SYT6 expression in non-cortical neuronal populations not comprehensively mapped"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for SYT6's lack of Ca²⁺-dependent lipid binding, the SNARE partners and fusogenic mechanism at dendritic exocytic sites, whether the sperm phospho-cycle operates in neurons, and the physiological consequences of SYT6 loss in vivo (no knockout phenotype has been reported).","evidence":"","pmids":[],"confidence":"High","gaps":["No SYT6 knockout mouse phenotype reported","No high-resolution structure of SYT6 C2 domains available","Molecular mechanism linking SYT6 to endosomal versus biosynthetic vesicle selectivity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,8]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,5,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,5,6]}],"complexes":[],"partners":["STX1A","NRXN1","SYT3","SYT5","SYT10","CPLX1","PRKCB","PPP3CA"],"other_free_text":[]},"mechanistic_narrative":"Synaptotagmin-6 (SYT6) is a dual-C2-domain transmembrane protein that functions as a calcium-regulated exocytic sensor in both neuronal and non-neuronal secretory systems. Unlike classical synaptotagmins, its C2A domain lacks Ca²⁺-dependent phospholipid binding, yet the protein interacts with clathrin-AP2, syntaxins, neurexins, and calmodulin through its C2 domains and conserved C-terminal motifs, and forms disulfide-linked homo- and heterodimers via N-terminal cysteine residues [PMID:7791877, PMID:8901523, PMID:10531343]. In human sperm, SYT6 localizes to the outer acrosomal membrane where PKCβII-mediated phosphorylation of polybasic threonine residues in C2A and C2B maintains a primed state, and calcineurin-dependent dephosphorylation at these sites triggers acrosomal exocytosis in a temporally regulated manner [PMID:11437455, PMID:16111671, PMID:20551332]. In hippocampal neurons, SYT6 selectively mediates complexin-dependent, activity-driven release of endosomal (recycled) BDNF from postsynaptic dendrites, a function not shared by other synaptotagmin isoforms and distinct from the release of de novo–synthesized BDNF [PMID:26216953]."},"prefetch_data":{"uniprot":{"accession":"Q5T7P8","full_name":"Synaptotagmin-6","aliases":["Synaptotagmin VI","SytVI"],"length_aa":510,"mass_kda":57.3,"function":"May be involved in Ca(2+)-dependent exocytosis of secretory vesicles through Ca(2+) and phospholipid binding to the C2 domain or may serve as Ca(2+) sensors in the process of vesicular trafficking and exocytosis. May mediate Ca(2+)-regulation of exocytosis in acrosomal reaction in sperm (By similarity)","subcellular_location":"Cytoplasm, cytosol; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q5T7P8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYT6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SYT6","total_profiled":1310},"omim":[{"mim_id":"607718","title":"SYNAPTOTAGMIN 6; SYT6","url":"https://www.omim.org/entry/607718"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":7.4},{"tissue":"pancreas","ntpm":2.9}],"url":"https://www.proteinatlas.org/search/SYT6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q5T7P8","domains":[{"cath_id":"2.60.40.150","chopping":"232-356","consensus_level":"high","plddt":90.7147,"start":232,"end":356},{"cath_id":"2.60.40.150","chopping":"365-496","consensus_level":"high","plddt":94.8468,"start":365,"end":496}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T7P8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T7P8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T7P8-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYT6","jax_strain_url":"https://www.jax.org/strain/search?query=SYT6"},"sequence":{"accession":"Q5T7P8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T7P8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T7P8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T7P8"}},"corpus_meta":[{"pmid":"22371606","id":"PMC_22371606","title":"Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death.","date":"2012","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22371606","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26216953","id":"PMC_26216953","title":"Activity-dependent BDNF release via endocytic pathways is regulated by synaptotagmin-6 and complexin.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26216953","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20575059","id":"PMC_20575059","title":"Molecular analysis of neocortical layer structure in the ferret.","date":"2010","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/20575059","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18639284","id":"PMC_18639284","title":"Identification of novel epigenetic markers for clear cell renal cell carcinoma.","date":"2008","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/18639284","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21438024","id":"PMC_21438024","title":"Methyl-CpG binding column-based identification of nine genes hypermethylated in colorectal cancer.","date":"2011","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/21438024","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36654170","id":"PMC_36654170","title":"Chromosome-scale genomes provide new insights into subspecies divergence and evolutionary characteristics of the giant panda.","date":"2021","source":"Science bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/36654170","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28948304","id":"PMC_28948304","title":"Histological analysis and identification of spermatogenesis-related genes in 2-, 6-, and 12-month-old sheep testes.","date":"2017","source":"Die Naturwissenschaften","url":"https://pubmed.ncbi.nlm.nih.gov/28948304","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39456006","id":"PMC_39456006","title":"Repetitive transcranial magnetic stimulation alleviates motor impairment in Parkinson's disease: association with peripheral inflammatory regulatory T-cells and SYT6.","date":"2024","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/39456006","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32266715","id":"PMC_32266715","title":"A logical relationship for schizophrenia, bipolar, and major depressive disorder. Part 1: Evidence from chromosome 1 high density association screen.","date":"2020","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/32266715","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34617601","id":"PMC_34617601","title":"Characterization and manipulation of Corticothalamic neurons in associative cortices using Syt6-Cre transgenic mice.","date":"2021","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34617601","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39564730","id":"PMC_39564730","title":"Blood Plasma Methylated DNA Markers in the Detection of Lymphoma: Discovery, Validation, and Clinical Pilot.","date":"2024","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/39564730","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33819195","id":"PMC_33819195","title":"Maternal high sugar and fat diet benefits offspring brain function via targeting on the gut-brain axis.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33819195","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40898655","id":"PMC_40898655","title":"A pilot study on DNA methylation changes for non-invasive molecular diagnostics in heart failure.","date":"2025","source":"ESC heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/40898655","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7791877","id":"PMC_7791877","title":"Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins.","date":"1995","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/7791877","citation_count":552,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23251661","id":"PMC_23251661","title":"Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23251661","citation_count":312,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17207965","id":"PMC_17207965","title":"hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes.","date":"2007","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/17207965","citation_count":222,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10531343","id":"PMC_10531343","title":"Conserved N-terminal cysteine motif is essential for homo- and heterodimer formation of synaptotagmins III, V, VI, and X.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10531343","citation_count":151,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16710414","id":"PMC_16710414","title":"The DNA sequence and biological annotation of human chromosome 1.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16710414","citation_count":144,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21832049","id":"PMC_21832049","title":"Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832049","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23942779","id":"PMC_23942779","title":"A genome-wide association study of behavioral disinhibition.","date":"2013","source":"Behavior genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23942779","citation_count":91,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32707033","id":"PMC_32707033","title":"Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32707033","citation_count":88,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25184681","id":"PMC_25184681","title":"Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage.","date":"2014","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25184681","citation_count":86,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32814053","id":"PMC_32814053","title":"Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32814053","citation_count":79,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11437455","id":"PMC_11437455","title":"Synaptotagmin VI participates in the acrosome reaction of human spermatozoa.","date":"2001","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/11437455","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11543631","id":"PMC_11543631","title":"Genomic analysis of synaptotagmin genes.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11543631","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24623722","id":"PMC_24623722","title":"Systematic identification of pathological lamin A interactors.","date":"2014","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/24623722","citation_count":56,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23319801","id":"PMC_23319801","title":"Identification of inherited genetic variations influencing prognosis in early-onset breast cancer.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23319801","citation_count":40,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8901523","id":"PMC_8901523","title":"Mirror image motifs mediate the interaction of the COOH terminus of multiple synaptotagmins with the neurexins and calmodulin.","date":"1996","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8901523","citation_count":36,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20551332","id":"PMC_20551332","title":"Calcineurin-mediated dephosphorylation of synaptotagmin VI is necessary for acrosomal exocytosis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20551332","citation_count":29,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16111671","id":"PMC_16111671","title":"Protein kinase C-mediated phosphorylation of the two polybasic regions of synaptotagmin VI regulates their function in acrosomal exocytosis.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16111671","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21244100","id":"PMC_21244100","title":"Protein array based interactome analysis of amyloid-β indicates an inhibition of protein translation.","date":"2011","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/21244100","citation_count":24,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"40437099","id":"PMC_40437099","title":"EndoMAP.v1 charts the structural landscape of human early endosome complexes.","date":"2025","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/40437099","citation_count":6,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8659,"output_tokens":1290,"usd":0.022663},"stage2":{"model":"claude-opus-4-6","input_tokens":4489,"output_tokens":1720,"usd":0.098168},"total_usd":0.35396,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":21315,"output_tokens":4810,"usd":0.068047},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7076,"output_tokens":2987,"usd":0.165082}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Synaptotagmin-6 (Syt6) is required for activity-induced release of endocytosed BDNF from postsynaptic dendritic endosomes in cultured hippocampal neurons; knockdown of Syt6 specifically impaired activity-dependent secretion of endosomal BDNF-quantum dot conjugates, while activity-independent secretion and release of endogenously synthesized BDNF were unaffected.\",\n      \"method\": \"shRNA knockdown of Syt6 in cultured hippocampal neurons combined with quantum-dot-tagged BDNF (BDNF-QD) live imaging and activity-induced secretion assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with specific phenotypic readout (activity-dependent endosomal BDNF release), multiple isoform controls, and functional rescue; single lab but multiple orthogonal approaches (QD tracking, isoform screen, KD)\",\n      \"pmids\": [\"26216953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"REST binds the promoter of the syt6 gene in hippocampal neurons following ischemic insult, recruits a repressive chromatin-remodeling complex (CoREST, mSin3A, HDAC1/2, G9a, MeCP2), and silences syt6 expression through epigenetic remodeling; RNAi depletion of REST in vivo prevents these modifications and restores syt6 mRNA/protein levels.\",\n      \"method\": \"ChIP of REST/CoREST/HDAC1-2/G9a/MeCP2 at syt6 promoter in ischemia model; RNAi-mediated REST knockdown in vivo with RT-PCR and western blot validation of target gene expression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and in vivo RNAi with expression rescue, but syt6 is one of several targets; mechanistic link is primarily to REST-mediated repression rather than Syt6 function per se\",\n      \"pmids\": [\"22371606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Syt6 is expressed in corticothalamic neurons (layer 6 and, to a lesser extent, layer 5) of the prefrontal and other associative cortices; optogenetic stimulation of Syt6-Cre+ neurons in the prefrontal cortex induces oscillatory local field potential activity resembling cortical downstates, establishing a functional role for this neuron population in cortical network dynamics.\",\n      \"method\": \"Syt6-Cre transgenic mouse line with Cre-mediated reporter characterization, immunohistochemistry, axon varicosity quantification, and in vivo optogenetic stimulation with LFP recording\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo optogenetic manipulation with electrophysiological readout, but finding is at the circuit/cell-type level rather than molecular mechanism of Syt6 protein itself\",\n      \"pmids\": [\"34617601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Syt6 was identified as a hub-node protein mechanistically linked to regulatory T-cell (Treg) modulation and rTMS therapeutic effects in an MPTP mouse model of Parkinson's disease; virus-mediated RNA interference of Syt6 in MPTP mice blocked the Treg-associated and motor-recovery benefits of rTMS, placing Syt6 downstream of rTMS in a neuroinflammatory pathway.\",\n      \"method\": \"Quantitative proteomics to identify hub proteins; AAV-mediated RNA interference of Syt6 in MPTP mice with flow cytometry (Tregs), immunohistochemistry (TH neurons), and behavioral motor assessment\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, in vivo KD with phenotypic readout but no direct biochemical mechanism of Syt6 action established\",\n      \"pmids\": [\"39456006\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYT6 functions as a calcium sensor isoform that specifically mediates activity-dependent release of endosomal BDNF from postsynaptic dendrites in hippocampal neurons (acting together with complexin), is transcriptionally silenced by REST-dependent epigenetic remodeling at its promoter following ischemic insult, and marks a defined population of layer 6 corticothalamic projection neurons whose optogenetic activation drives cortical oscillatory network activity.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- [Retrieved 1] PMID:22371606 — REST/epigenetic study; SYT6 is one of ~8 genes mentioned as a REST target, not the focus. The paper establishes REST-mediated silencing of *syt6* among other genes → KEEP (mechanistic finding about SYT6 regulation)\n- [Retrieved 2] PMID:26216953 — Directly about Syt6 role in BDNF release → KEEP\n- [Retrieved 3] PMID:20575059 — SYT6 used as a layer marker, expression pattern only → EXCLUDE (no mechanism)\n- [Retrieved 4] PMID:18639284 — SYT6 hypermethylation in cancer, expression/biomarker → EXCLUDE\n- [Retrieved 5] PMID:21438024 — SYT6 hypermethylation in CRC, expression/biomarker → EXCLUDE\n- [Retrieved 6] PMID:36654170 — Giant panda genomics; SYT6 changes mentioned speculatively for fertility → EXCLUDE (no direct mechanism)\n- [Retrieved 7] PMID:28948304 — Sheep spermatogenesis transcriptomics, SYT6 expression only → EXCLUDE\n- [Retrieved 8] PMID:39456006 — rTMS/PD study; Syt6 identified as hub protein via proteomics, RNA interference validates role → KEEP (limited mechanism)\n- [Retrieved 9] PMID:32266715 — GWAS association study → EXCLUDE\n- [Retrieved 10] PMID:34617601 — Syt6-Cre transgenic characterization; functional optogenetic stimulation of Syt6+ neurons → KEEP (localization + functional consequence)\n- [Retrieved 11] PMID:39564730 — Lymphoma methylation biomarker → EXCLUDE\n- [Retrieved 12] PMID:33819195 — Maternal diet/gut-brain; Syt6 expression change only → EXCLUDE\n- [Retrieved 13] PMID:40898655 — Heart failure methylation biomarker → EXCLUDE\n\n**Gene2pubmed papers:**\n- PMID:12477932 — MGC cDNA sequencing, no mechanism → EXCLUDE\n- PMID:26186194 — BioPlex interactome; SYT6 appears in large-scale AP-MS → KEEP (interaction data)\n- PMID:28514442 — BioPlex 2.0 → KEEP (interaction data)\n- PMID:25416956 — HuRI interactome → KEEP (interaction data)\n- PMID:32296183 — HuRI reference → KEEP\n- PMID:14702039 — FLJ cDNA sequencing → EXCLUDE\n- PMID:33961781 — BioPlex 3.0 → KEEP\n- PMID:21873635 — GO annotation, no mechanism → EXCLUDE\n- PMID:7791877 — Li et al. 1995, foundational Syt characterization including Syt VI C2 domains, phospholipid binding, AP2/syntaxin interactions → KEEP\n- PMID:16344560 — Alternative promoters, genomic → EXCLUDE\n- PMID:23251661 — GWAS obesity → EXCLUDE\n- PMID:17207965 — ORFeome resource → EXCLUDE\n- PMID:10531343 — Fukuda 1999, Syt III/V/VI/X homodimerization via N-terminal cysteines → KEEP\n- PMID:16710414 — Chr1 sequence annotation → EXCLUDE\n- PMID:21832049 — TPPP/p25 interactions, SYT6 not a focus → EXCLUDE\n- PMID:23942779 — GWAS behavioral disinhibition → EXCLUDE\n- PMID:32707033 — Kinase interaction network → EXCLUDE\n- PMID:25184681 — BRCA1 interactors → EXCLUDE\n- PMID:32814053 — ND interactome, SYT6 not focus → EXCLUDE\n- PMID:11437455 — Michaut 2001, Syt VI in acrosome reaction → KEEP\n- PMID:11543631 — Craxton 2001, genomic analysis of Syt genes → KEEP (structural/genomic characterization)\n- PMID:24623722 — Lamin A interactors → EXCLUDE\n- PMID:23319801 — GWAS breast cancer prognosis → EXCLUDE\n- PMID:8901523 — Perin 1996, Syt6 C-terminus interaction with neurexins and calmodulin → KEEP\n- PMID:20551332 — Calcineurin dephosphorylation of Syt VI in acrosomal exocytosis → KEEP\n- PMID:16111671 — PKC phosphorylation of Syt VI polybasic regions → KEEP\n- PMID:21244100 — Amyloid-β protein array; SYT6 not focus → EXCLUDE\n- PMID:40437099 — EndoMAP endosome interactome; SYT6 not focus → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Synaptotagmin VI (Syt6) shares the common synaptotagmin domain architecture (single transmembrane region + two C2 domains). The first C2 domain of Syt VI does NOT bind phospholipids in a Ca2+-dependent manner (unlike Syt I, II, III, V, VII). All Syt isoforms tested, including Syt VI, interact with clathrin-AP2 (Kd = 0.1–1.0 nM) and with neural and non-neural syntaxins via their cytoplasmic C2 domain region.\",\n      \"method\": \"In vitro binding assays, Ca2+-dependent phospholipid binding assays, clathrin-AP2 pull-down, syntaxin interaction assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical assays with multiple isoforms compared; foundational paper >550 citations\",\n      \"pmids\": [\"7791877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The C-terminus of Syt6 (synaptotagmin 6) interacts with neurexins in a calcium-independent manner, mediated by two mirror-image sequence motifs (Leu-X-His-Trp and Trp-His-X-Leu) in the C-terminal 34 amino acids. The same C-terminal domain also mediates calcium-dependent enrichment of calmodulin via the first of these motifs. Deletion or substitution of residues in these motifs greatly reduces neurexin binding.\",\n      \"method\": \"Affinity purification from solubilized brain membranes, recombinant protein binding assays, site-directed mutagenesis, 125I-calmodulin binding\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution with mutagenesis identifying specific residues; multiple binding partners tested\",\n      \"pmids\": [\"8901523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Synaptotagmin VI (along with Syt III, V, and X) forms beta-mercaptoethanol-sensitive homodimers and heterodimers via a conserved N-terminal cysteine motif (three cysteines at positions ~10, 21, and 33). Site-directed mutagenesis of the first cysteine residue abolishes stable homodimer formation of Syt VI and heterodimer formation between Syt VI and Syt III, V, or X.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, reducing agent sensitivity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis combined with co-IP clearly identifies specific cysteine residues; multiple isoforms tested\",\n      \"pmids\": [\"10531343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Synaptotagmin VI is localized to the outer acrosomal membrane of human sperm. A specific anti-Syt VI antibody and a recombinant GST fusion protein containing the C2A and C2B domains of Syt VI both abrogated calcium-triggered acrosomal exocytosis in permeabilized spermatozoa, demonstrating that Syt VI is required for this secretory process. Syt VI is also necessary for Rab3A-promoted acrosomal exocytosis at low calcium concentrations. Phorbol ester-dependent phosphorylation of the C2A–C2B fusion protein abolished its inhibitory effect on exocytosis.\",\n      \"method\": \"Western blot, immunocytochemistry (optical and electron microscopy), function-blocking antibody assays in permeabilized sperm, recombinant protein inhibition assays, in vitro phosphorylation\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization + antibody blocking + recombinant domain inhibition + phosphorylation rescue) in single study\",\n      \"pmids\": [\"11437455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Genomic analysis identified human homologues for all known rodent synaptotagmin genes, establishing the full genomic structure of the synaptotagmin family. Comparison of genomic structures clarified the phylogeny of different subgroups, including Syt6, and revealed alternative splicing possibilities.\",\n      \"method\": \"TBLASTn genomic database searches, comparative genomic structure analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/comparative genomics only, no direct functional experiment\",\n      \"pmids\": [\"11543631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Protein kinase C betaII (PKCbetaII) phosphorylates Syt VI at Thr418 and/or Thr419 in the polybasic region (KKKTTIK) of the C2B domain, and at Thr284 in the polybasic region (KCKLQTR) of the C2A domain. PKC-mediated phosphorylation of either C2 domain abolishes their inhibitory effect on acrosomal exocytosis in permeabilized spermatozoa. An antibody recognizing the phosphorylated C2B polybasic region detected endogenous phosphorylated Syt VI in the sperm acrosomal region, and immunolabeling decreased upon sperm stimulation, indicating dephosphorylation occurs during exocytosis.\",\n      \"method\": \"Site-directed mutagenesis, in vitro phosphorylation with purified PKCbetaII, function-blocking assays in permeabilized sperm, phospho-specific antibody immunolabeling\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-directed mutagenesis identifying specific phosphorylation sites combined with functional exocytosis assays and endogenous protein detection\",\n      \"pmids\": [\"16111671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Calcineurin (a calcium-dependent phosphatase) dephosphorylates Syt VI at the polybasic region of its C2B domain during the early stages of human sperm acrosomal exocytosis. This dephosphorylation is required for progression of exocytosis: calcineurin inhibition (cyclosporin A) blocked exocytosis, and an inhibitor-insensitive catalytically active calcineurin domain rescued it. Premature calcineurin-driven dephosphorylation before stimulation inhibited exocytosis, an effect rescued by a phosphomimetic Syt VI C2B-T418E/T419E mutant, demonstrating that temporally regulated dephosphorylation of Syt VI is essential.\",\n      \"method\": \"Calcineurin inhibitor (cyclosporin A) functional assays in permeabilized sperm, recombinant active calcineurin domain rescue, in vitro dephosphorylation of recombinant Syt VI C2B, phosphomimetic mutant rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal approaches including enzyme inhibition, active domain rescue, substrate mutagenesis, and phosphomimetic rescue\",\n      \"pmids\": [\"20551332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Following ischemic insult, the transcriptional repressor REST (RE-1 silencing transcription factor) binds the syt6 gene promoter among a subset of target genes in hippocampal neurons. REST assembles a repressor complex containing CoREST, mSin3A, histone deacetylases 1 and 2, G9a histone methyltransferase, and MeCP2 at the syt6 promoter, orchestrating epigenetic silencing and reducing Syt6 mRNA and protein levels. RNAi-mediated depletion of REST prevented these epigenetic modifications and restored syt6 expression.\",\n      \"method\": \"ChIP (chromatin immunoprecipitation), RNAi knockdown in vivo, mRNA/protein quantification, in vivo hippocampal injection of dominant-negative REST\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + RNAi rescue in vivo; Syt6 is one of ~8 genes examined, not the primary focus\",\n      \"pmids\": [\"22371606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Among eight synaptotagmin isoforms examined, only Syt6 knockdown impaired activity-induced release of endocytosed (exogenous) BDNF-quantum dot conjugates from postsynaptic dendrites of cultured hippocampal neurons. Repetitive neuronal spiking triggered BDNF-QD release preferentially at postsynaptic sites in a glutamate receptor-dependent manner, and this required Syt6 (and complexin 1/2). In contrast, activity-induced release of endogenously synthesized BDNF did not depend on Syt6, indicating Syt6 specifically regulates exocytic release of endosomal (recycled) BDNF from dendrites.\",\n      \"method\": \"shRNA knockdown of individual Syt isoforms, quantum dot-tagged BDNF live imaging, activity-dependent secretion assays in cultured hippocampal neurons, glutamate receptor pharmacology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective isoform knockdown screen across 8 Syts combined with live imaging; isoform specificity rigorously demonstrated\",\n      \"pmids\": [\"26216953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Syt6-Cre transgenic mice express Cre recombinase (and thus mark Syt6-expressing cells) predominantly in layer 6 corticothalamic neurons (CTn) and to a lesser extent layer 5 CTn in prefrontal, motor, cingulate, and retrosplenial cortices. Cortical expression begins embryonically and reaches the adult pattern by postnatal day 15. Optogenetic stimulation of Syt6-Cre+ neurons in prefrontal cortex induced oscillatory local field potential activity resembling cortical downstates observed during slow-wave sleep or quiet waking.\",\n      \"method\": \"Cre-reporter lineage tracing, immunohistochemistry, axon varicosity quantification, in vivo optogenetic stimulation with local field potential recording\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by reporter expression with functional consequence demonstrated by optogenetic stimulation\",\n      \"pmids\": [\"34617601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Quantitative proteomic analysis of MPTP-induced Parkinson's disease mouse brain identified Syt6 as a hub node protein associated with regulatory T-cell (Treg) networks and rTMS treatment response. Virus-mediated RNA interference of Syt6 in MPTP mice was used to validate its functional role: Syt6 knockdown affected the therapeutic outcomes of rTMS on motor function and Treg modulation.\",\n      \"method\": \"Quantitative proteomics (label-free), virus-mediated RNAi in vivo, motor behavior assessment, flow cytometry of Tregs\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proteomics identification + in vivo RNAi with behavioral readout, but molecular mechanism downstream of Syt6 not defined\",\n      \"pmids\": [\"39456006\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Synaptotagmin 6 (SYT6) is a membrane protein with two C2 domains that lacks Ca2+-dependent phospholipid binding through its C2A domain but interacts with clathrin-AP2, syntaxins, and neurexins (via conserved C-terminal motifs) and calmodulin (Ca2+-dependently); it forms disulfide-linked homodimers and heterodimers with Syt III/V/X via N-terminal cysteine residues; in human sperm it localizes to the outer acrosomal membrane and is an essential component of the Ca2+-triggered acrosomal exocytosis machinery, regulated by PKCbetaII-mediated phosphorylation of conserved threonines in the C2A and C2B polybasic regions and by calcineurin-mediated dephosphorylation at the onset of exocytosis; in neurons it is expressed in layer 6 corticothalamic neurons and selectively mediates activity-dependent release of endosomal (recycled) BDNF from postsynaptic dendrites in a complexin-dependent manner; and its gene is subject to REST-dependent epigenetic silencing following ischemic insult.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SYT6 is a synaptotagmin family calcium-sensor isoform that mediates activity-dependent release of endosomal BDNF from postsynaptic dendrites in hippocampal neurons; knockdown of SYT6 specifically impairs activity-induced secretion of endocytosed BDNF without affecting activity-independent or biosynthetic BDNF release [PMID:26216953]. Following ischemic insult, the syt6 promoter is bound by the transcriptional repressor REST, which recruits a repressive chromatin-remodeling complex (CoREST, mSin3A, HDAC1/2, G9a, MeCP2) to epigenetically silence syt6 expression; in vivo REST knockdown restores syt6 mRNA and protein levels [PMID:22371606]. SYT6 also marks layer 6 corticothalamic projection neurons, and optogenetic activation of Syt6-Cre+ neurons in the prefrontal cortex drives oscillatory cortical network activity resembling downstates [PMID:34617601].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing how syt6 expression is controlled in pathological states: REST was shown to bind the syt6 promoter after ischemia and recruit a repressive epigenetic complex to silence syt6, revealing that syt6 is subject to activity-dependent transcriptional repression in neurons.\",\n      \"evidence\": \"ChIP for REST and co-repressor complex components at the syt6 promoter in a rodent ischemia model, combined with in vivo RNAi-mediated REST knockdown and RT-PCR/western blot validation\",\n      \"pmids\": [\"22371606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequences of syt6 silencing after ischemia were not tested directly\",\n        \"Whether syt6 silencing contributes to ischemic neuronal death or is neuroprotective is unknown\",\n        \"Other transcription factors that control basal syt6 expression are not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the molecular function of SYT6: among synaptotagmin isoforms, SYT6 was identified as the specific calcium sensor required for activity-dependent release of endocytosed BDNF from postsynaptic dendritic endosomes, establishing a unique postsynaptic secretory role distinct from presynaptic exocytosis.\",\n      \"evidence\": \"shRNA knockdown of Syt6 in cultured hippocampal neurons with quantum-dot-tagged BDNF live imaging, isoform-specific controls, and functional rescue\",\n      \"pmids\": [\"26216953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether SYT6 acts as a direct Ca²⁺-binding effector on endosomal membranes or requires additional cofactors beyond complexin is unresolved\",\n        \"No reconstitution of SYT6-mediated endosomal fusion in vitro\",\n        \"In vivo validation of the BDNF secretion phenotype (e.g., in Syt6 knockout mice) has not been reported\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linking SYT6 expression to circuit-level function: Syt6 was found to define a corticothalamic layer 6 neuronal population whose optogenetic activation drives cortical oscillatory downstates, establishing SYT6 as a cell-type marker with functional network consequences.\",\n      \"evidence\": \"Syt6-Cre transgenic mouse with Cre-dependent reporters, immunohistochemistry, and in vivo optogenetic stimulation with LFP recording in prefrontal cortex\",\n      \"pmids\": [\"34617601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SYT6 protein itself is mechanistically required for the corticothalamic circuit function or merely marks the cell type is unknown\",\n        \"Molecular partners of SYT6 in layer 6 neurons have not been identified\",\n        \"The relationship between SYT6-mediated BDNF release and layer 6 corticothalamic function is unexplored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending SYT6 to neuroinflammatory signaling: knockdown of Syt6 in an MPTP Parkinson's model blocked Treg modulation and motor recovery induced by rTMS, suggesting SYT6 participates in a neuroinflammatory regulatory pathway.\",\n      \"evidence\": \"Quantitative proteomics followed by AAV-mediated Syt6 RNAi in MPTP mice, with flow cytometry for Tregs and behavioral motor assessment\",\n      \"pmids\": [\"39456006\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical mechanism linking SYT6 to Treg modulation or neuroinflammation was established\",\n        \"Finding is from a single lab without independent replication\",\n        \"Whether the effect is mediated through SYT6's known endosomal secretion function or a novel mechanism is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which SYT6 couples Ca²⁺ sensing to endosomal membrane fusion remains unresolved: no structural data, no reconstituted fusion assay, and no in vivo loss-of-function model (knockout mouse) have been reported for SYT6's postsynaptic secretory function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of SYT6 C2 domains with Ca²⁺ or membrane\",\n        \"No Syt6 knockout mouse phenotype reported\",\n        \"Whether SYT6 functions in regulated secretion in non-neuronal cell types is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0008289\",\n        \"supporting_discovery_ids\": [0]\n      },\n      {\n        \"term_id\": \"GO:0140299\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005768\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-5653656\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"REST\",\n      \"BDNF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Synaptotagmin-6 (SYT6) is a dual-C2-domain transmembrane protein that functions as a calcium-regulated exocytic sensor in both neuronal and non-neuronal secretory systems. Unlike classical synaptotagmins, its C2A domain lacks Ca²⁺-dependent phospholipid binding, yet the protein interacts with clathrin-AP2, syntaxins, neurexins, and calmodulin through its C2 domains and conserved C-terminal motifs, and forms disulfide-linked homo- and heterodimers via N-terminal cysteine residues [PMID:7791877, PMID:8901523, PMID:10531343]. In human sperm, SYT6 localizes to the outer acrosomal membrane where PKCβII-mediated phosphorylation of polybasic threonine residues in C2A and C2B maintains a primed state, and calcineurin-dependent dephosphorylation at these sites triggers acrosomal exocytosis in a temporally regulated manner [PMID:11437455, PMID:16111671, PMID:20551332]. In hippocampal neurons, SYT6 selectively mediates complexin-dependent, activity-driven release of endosomal (recycled) BDNF from postsynaptic dendrites, a function not shared by other synaptotagmin isoforms and distinct from the release of de novo–synthesized BDNF [PMID:26216953].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the biochemical identity of SYT6 resolved whether all synaptotagmin isoforms share the canonical Ca²⁺-dependent phospholipid-binding activity: SYT6's C2A domain does not bind phospholipids in a Ca²⁺-dependent manner, yet the protein retains high-affinity interactions with clathrin-AP2 and syntaxins, suggesting a specialized regulatory role.\",\n      \"evidence\": \"In vitro Ca²⁺-dependent phospholipid binding assays and pull-down assays comparing multiple Syt isoforms\",\n      \"pmids\": [\"7791877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the SYT6 C2A domain explaining its divergent lipid-binding properties\",\n        \"Functional consequence of the AP2/syntaxin interactions for SYT6 specifically was not tested in cells\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of neurexin and calmodulin as C-terminal binding partners, mediated by mirror-image LXHW/WHXL motifs, revealed a molecular interface coupling SYT6 to synaptic cell-adhesion molecules and Ca²⁺/calmodulin signaling.\",\n      \"evidence\": \"Affinity purification from brain membranes, recombinant binding assays, and site-directed mutagenesis of C-terminal motifs\",\n      \"pmids\": [\"8901523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological relevance of the SYT6–neurexin interaction in intact synapses not demonstrated\",\n        \"Whether calmodulin binding modulates SYT6 exocytic function remains untested\"\n      ]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Discovery that SYT6 forms disulfide-linked homodimers and heterodimers (with SYT3, SYT5, SYT10) via conserved N-terminal cysteines established a quaternary structural principle for the Syt family and raised the possibility that heteromeric complexes diversify exocytic regulation.\",\n      \"evidence\": \"Co-immunoprecipitation with reducing-agent sensitivity and cysteine mutagenesis\",\n      \"pmids\": [\"10531343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether heterodimerization occurs in vivo in native tissues is unresolved\",\n        \"Functional consequence of dimerization for exocytosis not tested\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Localization of SYT6 to the outer acrosomal membrane and demonstration that anti-SYT6 antibodies and recombinant C2 domains block Ca²⁺-triggered acrosomal exocytosis established the first cellular function for SYT6 as an essential exocytic calcium sensor in sperm.\",\n      \"evidence\": \"Immunocytochemistry, function-blocking antibody and recombinant-domain inhibition assays in permeabilized human spermatozoa\",\n      \"pmids\": [\"11437455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Genetic loss-of-function confirmation (knockout) not available\",\n        \"SNARE complex partners at the acrosomal membrane not defined\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of PKCβII as the kinase that phosphorylates specific threonines in the C2A and C2B polybasic regions of SYT6 explained how phosphorylation relieves the inhibitory effect of C2 domains on exocytosis and implicated a phosphorylation-dependent priming mechanism.\",\n      \"evidence\": \"In vitro phosphorylation with purified PKCβII, site-directed mutagenesis (Thr284, Thr418/419), functional exocytosis assays in permeabilized sperm, phospho-specific antibody detection\",\n      \"pmids\": [\"16111671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal structure of phosphorylated versus unphosphorylated C2 domains not determined\",\n        \"Whether other kinases contribute in vivo unknown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that calcineurin-mediated dephosphorylation of SYT6 C2B polybasic threonines is temporally required at the onset of exocytosis completed a phosphorylation–dephosphorylation cycle model in which PKCβII primes and calcineurin activates SYT6-dependent membrane fusion.\",\n      \"evidence\": \"Cyclosporin A inhibition, catalytically active calcineurin rescue, in vitro dephosphorylation, and phosphomimetic T418E/T419E mutant rescue in permeabilized sperm\",\n      \"pmids\": [\"20551332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether this phospho-cycle operates in neuronal exocytosis is unknown\",\n        \"Direct structural basis for how dephosphorylation enables membrane fusion not established\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that REST recruits a repressor complex (CoREST, mSin3A, HDAC1/2, G9a, MeCP2) to the SYT6 promoter after ischemia, silencing its expression, linked SYT6 to epigenetic regulation in neuronal injury, though SYT6 was one of several REST targets studied.\",\n      \"evidence\": \"ChIP and in vivo RNAi of REST in hippocampal neurons following ischemia\",\n      \"pmids\": [\"22371606\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of SYT6 downregulation specifically (vs. other REST targets) for ischemic pathology not isolated\",\n        \"Whether REST regulation of SYT6 occurs under non-pathological conditions not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A selective isoform-specific knockdown screen revealed that SYT6 — uniquely among eight synaptotagmins — is required for activity-dependent postsynaptic release of endosomal (recycled) BDNF from hippocampal dendrites, establishing a neuronal exocytic function distinct from presynaptic vesicle fusion.\",\n      \"evidence\": \"shRNA knockdown of individual Syt isoforms combined with quantum-dot-tagged BDNF live imaging and pharmacological dissection in cultured hippocampal neurons\",\n      \"pmids\": [\"26216953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo confirmation of dendritic BDNF release dependence on SYT6 not yet reported\",\n        \"SNARE partners mediating the SYT6-dependent dendritic exocytic step are undefined\",\n        \"Mechanism by which SYT6 distinguishes endosomal versus de novo BDNF vesicles is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Lineage tracing with Syt6-Cre mice localized SYT6 expression predominantly to layer 6 corticothalamic neurons, and optogenetic activation of these neurons evoked cortical oscillations resembling slow-wave downstates, placing SYT6-expressing circuits in corticothalamic feedback control.\",\n      \"evidence\": \"Cre-reporter lineage tracing, immunohistochemistry, and in vivo optogenetic stimulation with LFP recording in prefrontal cortex\",\n      \"pmids\": [\"34617601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SYT6 protein function (vs. merely expression) is required for corticothalamic signaling not tested\",\n        \"SYT6 expression in non-cortical neuronal populations not comprehensively mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for SYT6's lack of Ca²⁺-dependent lipid binding, the SNARE partners and fusogenic mechanism at dendritic exocytic sites, whether the sperm phospho-cycle operates in neurons, and the physiological consequences of SYT6 loss in vivo (no knockout phenotype has been reported).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No SYT6 knockout mouse phenotype reported\",\n        \"No high-resolution structure of SYT6 C2 domains available\",\n        \"Molecular mechanism linking SYT6 to endosomal versus biosynthetic vesicle selectivity undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 5, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"STX1A\",\n      \"NRXN1\",\n      \"SYT3\",\n      \"SYT5\",\n      \"SYT10\",\n      \"CPLX1\",\n      \"PRKCB\",\n      \"PPP3CA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}