{"gene":"SYT11","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2018,"finding":"Synaptotagmin-11 (Syt11) is a physiological substrate of parkin (E3 ubiquitin ligase). Overexpression of full-length, but not C2B-truncated, Syt11 in dopaminergic neurons of the substantia nigra pars compacta impairs striatal dopamine release by inhibiting endocytosis and vesicle pool replenishment, causing dopaminergic neuron degeneration. Parkin deficiency leads to Syt11 accumulation and PD-like neurotoxicity, which is reversed by SYT11 knockdown or knockout in dopaminergic neurons.","method":"In vivo unilateral overexpression, conditional knockout, parkin-deficient mouse models, dopamine release measurements, motor behavior assays, immunoprecipitation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal in vivo and in vitro methods, genetic rescue experiments, replicated mechanistic link","pmids":["29311685"],"is_preprint":false},{"year":2016,"finding":"ATP13A2 depletion negatively regulates SYT11 at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by MYCBP2-induced ubiquitination of TSC2, leading to mTORC1 activation and decreased TFEB-mediated transcription of SYT11. Increased SYT11 protein turnover is regulated by its ubiquitination and degradation. Decreased SYT11 levels induce lysosomal dysfunction and impaired autophagosome degradation.","method":"siRNA knockdown, transcriptional assays, ubiquitination assays, lysosomal function assays, mTORC1/TFEB pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in a single rigorous study identifying the complete pathway","pmids":["27278822"],"is_preprint":false},{"year":2019,"finding":"Syt11 resides on abundant vesicles resembling trafficking endosomes (distinct from synaptic vesicles) in neurons. These vesicles recycle via the plasma membrane in an activity-dependent manner with slow, desynchronized exocytosis. Constitutive Syt11 knockout mice die shortly after birth. Conditional knockout in excitatory forebrain neurons impairs synaptic plasticity and memory without affecting fast neurotransmitter or peptide secretion, but reduces long-term synaptic potentiation.","method":"Conditional and constitutive knockout mice, live imaging, mass spectrometry (Syt11 interactome), electrophysiology, behavioral assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 — constitutive and conditional KO with multiple functional readouts, MS interactome, strong mechanistic conclusions","pmids":["30808661"],"is_preprint":false},{"year":2017,"finding":"Syt11 inhibits cytokine secretion (IL-6, TNF-α) and phagocytosis in microglia. Syt11 localizes to the trans-Golgi network and recycling endosomes, and is recruited to phagosomes. Syt11 knockdown increases NF-κB activation and cytokine synthesis/secretion capacity, and enhances phagocytosis including of α-synuclein fibrils. Overexpression of Syt11 suppresses these functions.","method":"siRNA knockdown, overexpression rescue, immunofluorescence localization, cytokine ELISA, phagocytosis assays, NF-κB activation assays","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, gain- and loss-of-function with rescue, subcellular localization tied to function","pmids":["28686317"],"is_preprint":false},{"year":2023,"finding":"Syt11 is palmitoylated at Cys39 and Cys40 (adjacent to its transmembrane domain) in mouse and human brain tissue and cultured cortical neurons. This palmitoylation localizes Syt11 to digitonin-insoluble intracellular membranes and protects it from endolysosomal degradation. Palmitoylation-mediated increase in Syt11 abundance enhances α-synuclein binding to intracellular membranes, decreasing physiologic tetrameric α-synuclein and increasing aggregation-prone monomeric α-synuclein. A palmitoylation-deficient mutant does not replicate these effects.","method":"Palmitoylation assays (acyl-RAC), site-directed mutagenesis, biochemical fractionation, α-synuclein tetramer/monomer quantification in neurons, overexpression of WT vs palmitoylation-deficient mutant","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis, biochemical reconstitution, multiple orthogonal methods establishing palmitoylation site and functional consequences","pmids":["36787382"],"is_preprint":false},{"year":2021,"finding":"Syt11 inhibits spontaneous neurotransmitter release by directly interacting with vti1a (a non-canonical SNARE protein that maintains spontaneous release). The C2A domain of Syt11 binds vti1a with high affinity. Syt11-KO hippocampal neurons show increased miniature EPSC frequency; vti1a knockdown reverses this phenotype, identifying vti1a as the main target.","method":"GST pull-down, co-immunoprecipitation, affinity purification, Syt11 knockout neurons, electrophysiology (mEPSC recording), vti1a knockdown epistasis","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding confirmed by multiple methods, epistasis experiment identifies vti1a as main target","pmids":["34599505"],"is_preprint":false},{"year":2023,"finding":"Syt11 inhibits synaptic vesicle (SV) endocytosis through direct, Ca2+-independent binding to endophilin A1 (EndoA1) via the C2B domain of Syt11 and the N-terminus of EndoA1. Syt11-KO accelerates SV endocytosis and vesicle recycling. A peptide (aa 314-336) from Syt11 C2B blocks Syt11-EndoA1 binding in vitro and in vivo, inhibiting SV endocytosis. EndoA1 knockdown reverses the Syt11-KO phenotype, establishing EndoA1 as the main inhibitory target of Syt11 in SV endocytosis.","method":"GST pull-down, co-immunoprecipitation, Syt11-KO mouse neurons, EndoA1 knockdown epistasis, peptide competition assays, electrophysiology at calyx of Held, live imaging","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding characterization with domain mapping, peptide inhibition, genetic epistasis, multiple orthogonal methods","pmids":["37474308"],"is_preprint":false},{"year":2024,"finding":"Syt11 binds both the auxiliary GABAB receptor (GBR) subunit KCTD16 and Cav2.2 Ca2+ channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, facilitating assembly of GBR/Cav2.2 signaling complexes. Syt11 also stabilizes GBRs and Cav2.2 at the neuronal plasma membrane by inhibiting constitutive internalization. Syt11-KO mice show deficits in presynaptic GBRs and Cav2.2, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition.","method":"Co-immunoprecipitation, proximity ligation, Syt11 KO mouse analysis, electrophysiology, live imaging, biochemical fractionation","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, KO mouse with multiple functional readouts, multiple orthogonal methods","pmids":["38698221"],"is_preprint":false},{"year":2019,"finding":"Syt11 regulates caveolae-mediated endocytosis and caveolar response to mechanical stimuli in astrocytes. Syt11-KO accelerates caveolae-mediated endocytosis, reduces caveolar structures on the cell surface, and impairs caveolar disassembly and astrocyte swelling during hypoosmotic stimuli. Syt11 directly interacts with cavin1 and EHD2 (but not caveolin-1), and its absence increases turnover of cavin1 and EHD2 and compromises membrane integrity. Live imaging showed Syt11 leaves caveolar structures before cavin1 during hypoosmotic stress.","method":"Syt11 KO astrocytes, live imaging, co-immunoprecipitation/pulldown, electron microscopy, osmotic stress assays, endocytosis assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — KO with defined phenotype, direct binding identified, live imaging with functional consequence","pmids":["31908017"],"is_preprint":false},{"year":2023,"finding":"Syt11 inhibits microglial immune responses in vivo. Inducible microglia-specific Syt11-cKO results in microglial activation and elevated cytokine mRNA. In a PD model, Syt11-cKO microglia show reduced migration to injection sites but enhanced phagocytosis of α-synuclein fibrils. Syt11 directly binds vti1a and vti1b via its linker domain; a competitive peptide derived from this domain induces cytokine secretion in WT microglia, phenocopying Syt11 KD.","method":"Inducible microglia-specific conditional KO, LPS and PD model in vivo, co-immunoprecipitation, peptide competition assay, cytokine measurements, phagocytosis assay","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with in vivo phenotype, direct binding with domain mapping and peptide inhibition, multiple orthogonal methods","pmids":["37924268"],"is_preprint":false},{"year":2022,"finding":"SYT11 functions as a scaffold protein in gastric cancer cells, binding both MKK7 and JNK1 to promote JNK1 phosphorylation. JNK activation leads to cJun activation and downstream expression of EMT-related genes (ANGPTL2, THBS4, Vimentin, JAM3). SYT11 knockdown reduces spheroid formation, tumor formation, and liver metastasis.","method":"Phospho-kinase array, co-immunoprecipitation, western blot, shRNA knockdown, mouse xenograft, liver metastasis model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP identifies complex, in vivo functional data, but single lab study","pmids":["35768842"],"is_preprint":false},{"year":2022,"finding":"Impad1 interacts directly with Syt11 (a vesicle trafficking protein) to modulate Golgi apparatus morphology and vesicular trafficking. This interaction alters the extracellular matrix and tumor microenvironment to promote lung cancer invasion and metastasis. Inhibiting either Impad1 or Syt11 disrupts the cancer cell secretome and reverses invasive/metastatic phenotype.","method":"Co-immunoprecipitation/interaction assays, in vitro and in vivo shRNA screens, Golgi morphology imaging, secretome analysis, invasion and metastasis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding interaction identified, functional KD with defined phenotype, but mechanistic detail is partial","pmids":["36170810"],"is_preprint":false},{"year":2014,"finding":"Syt11 interacts with components of the RNA-induced silencing complex (RISC) in pancreatic β-cells. The C2A domain of Syt11 interacts with the Q-SNARE Vti1a, while the C2B domain interacts with SND1, Ago2, and FMRP (RISC components). Binding of C2B to SND1 was shown to be direct via SND1's N-terminal tandem repeats.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation, domain-specific pulldowns, direct binding assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding established for some interactions, but functional consequences of RISC interaction not fully characterized","pmids":["24882364"],"is_preprint":false},{"year":2012,"finding":"Syt11 is expressed mainly in the brain and localizes to presynaptic neurotransmitter vesicles and plasma membrane (with some postsynaptic localization). Exogenously expressed Syt11 can form higher molecular weight complexes via its transmembrane domain. Syt11 is targeted to both dendrite and axon compartments, and is juxtaposed to postsynaptic markers in excitatory and inhibitory synapses. Both neuroligin-1 and neuroligin-2 recruit Syt11 in neuron co-culture.","method":"Immunocytochemistry, immunogold electron microscopy, subcellular fractionation, neuroligin recruitment assay, HEK293 expression","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization by electron microscopy, but limited functional consequence mapping","pmids":["22960622"],"is_preprint":false},{"year":2007,"finding":"Transcriptional activity of the Syt11 gene is affected by the number of 33-bp repeats in its promoter region (containing an Sp1 binding site), with excessive expression associated with schizophrenia. A SNP in the 5'UTR region where YY1 can bind also affects transcriptional activity of Syt11.","method":"Reporter/transient transcription assays, gel mobility shift assay, genetic association","journal":"American journal of medical genetics. Part B, Neuropsychiatric genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter assays establish promoter regulation, but functional consequence of altered expression is inferred","pmids":["17192956"],"is_preprint":false},{"year":2005,"finding":"Non-CpG methylation in the promoter region of syt11 reduces the binding of an Sp family transcription factor, thereby reducing syt11 expression. Cytosine residues in the minus strand of the promoter are partially methylated, and artificial methylation of these sites reduces reporter gene expression.","method":"Gel mobility shift assay, transient transcription assay with artificially methylated promoter, sequence analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — functional reporter and gel shift assays directly link non-CpG methylation to reduced Sp1 binding and transcription","pmids":["15777718"],"is_preprint":false},{"year":2020,"finding":"Syt11 is a short-lived protein degraded primarily by the ubiquitin-proteasome pathway (UPP) in neurons (half-life ~1.49 h). Degradation is accelerated under sustained neuronal activity in a parkin-dependent manner. In astrocytes, Syt11 has a faster turnover (half-life ~0.58 h) partially via UPP, but is degraded via a parkin-independent mechanism under both isoosmotic and hypoosmotic conditions.","method":"Cycloheximide chase, proteasome inhibitors, parkin overexpression/knockdown, neuronal activity manipulation, western blot","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — direct biochemical measurement of protein half-life, multiple conditions tested, parkin dependency established","pmids":["32976921"],"is_preprint":false},{"year":2024,"finding":"Syt11 deficiency in dopamine neurons during early adolescence (but not in adults) leads to persistent social deficits and schizophrenia-like behaviors by mediating dopamine over-transmission. Dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits with structural and functional alterations in the mPFC. D2R-targeting interventions presynaptically or postsynaptically show therapeutic effects on social deficits.","method":"Conditional Syt11 knockout in dopamine neurons (developmental stage-specific), electrophysiology, dopamine measurements, behavioral assays, mPFC structural/functional analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with stage-specific manipulation, multiple functional readouts, mechanistic pathway established","pmids":["39632880"],"is_preprint":false},{"year":2022,"finding":"Syt11 and Syt13 co-localize with insulin in insulin granules in β-cells. Downregulation of Syt11 in INS-1 832/13 cells increases basal and glucose-induced insulin secretion (suggesting an inhibitory role), without affecting exocytosis amplitude or Ca2+ currents. Downregulation of Syt13 decreases insulin secretion and abolishes forskolin-enhanced secretion.","method":"siRNA knockdown, ELISA, patch-clamp electrophysiology, confocal microscopy colocalization","journal":"Acta physiologica","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization and functional KD established, but mechanism of Syt11 inhibition of secretion not fully resolved","pmids":["35753051"],"is_preprint":false},{"year":2025,"finding":"VHL (an E3 ubiquitin ligase) binds SYT11 protein and promotes its proteasomal degradation by ubiquitination. VHL overexpression decreases SYT11 protein (not mRNA) and shortens its half-life; MG132 (proteasome inhibitor) reverses this. VHL-mediated SYT11 degradation downregulates SPINK1, which in turn inhibits gastric cancer cell growth and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, MG132 rescue, cycloheximide chase, transcriptome sequencing, knockdown/overexpression functional assays","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by co-IP, ubiquitination assay establishes mechanism, but single lab study","pmids":["40576306"],"is_preprint":false},{"year":2025,"finding":"Compensatory upregulation of Syt11 in parkin knockout mice during the suckling stage (but not in adults) conceals PD-associated phenotypes. Parkin knockdown in adult SNpc impairs dopamine release and causes motor deficits. Overexpression of Syt11 alone induces PD-like motor and non-motor impairments, impaired dopamine release and reuptake.","method":"Parkin KO and KD mouse models, Syt11 overexpression in SNpc, dopamine release measurements, motor behavior assays, western blot","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mouse models and rescue experiments, but single lab study","pmids":["39901263"],"is_preprint":false}],"current_model":"Synaptotagmin-11 (Syt11) is a Ca2+-independent vesicle-trafficking protein that acts as an inhibitory regulator of multiple membrane trafficking pathways: it suppresses spontaneous neurotransmitter release by binding vti1a via its C2A domain, inhibits synaptic vesicle endocytosis through direct interaction with endophilin A1 via its C2B domain, recruits GABAB receptors and Cav2.2 channels to post-Golgi vesicles via KCTD16 binding, inhibits cytokine secretion and phagocytosis in microglia via vti1a/vti1b interactions, and is regulated post-translationally as a substrate of parkin-mediated ubiquitination and by palmitoylation at Cys39/Cys40 (which protects it from endolysosomal degradation and promotes pathological α-synuclein monomerization); its accumulation due to parkin loss-of-function mediates dopaminergic neurotoxicity relevant to Parkinson's disease."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that non-CpG methylation within the SYT11 promoter reduces Sp-family transcription factor binding and transcription revealed an epigenetic layer controlling SYT11 expression levels.","evidence":"Gel shift and reporter assays with artificially methylated promoter constructs","pmids":["15777718"],"confidence":"Medium","gaps":["In vivo relevance of non-CpG methylation at endogenous SYT11 locus not demonstrated","No link to functional consequences of altered Syt11 protein levels"]},{"year":2007,"claim":"Identification that variable 33-bp repeat number in the SYT11 promoter modulates transcription via Sp1 binding, with a YY1-dependent 5′UTR SNP also affecting expression, connected SYT11 dosage variation to schizophrenia risk.","evidence":"Reporter assays, gel shift assays, and genetic association in schizophrenia cohorts","pmids":["17192956"],"confidence":"Medium","gaps":["Functional consequence of altered Syt11 expression in neurons not tested","Genetic association not replicated in independent cohorts within this study"]},{"year":2012,"claim":"Demonstrating that Syt11 localizes to presynaptic vesicles and plasma membrane at both excitatory and inhibitory synapses, and is recruited by neuroligins, established its synaptic identity as a vesicle-associated protein.","evidence":"Immunogold electron microscopy, subcellular fractionation, neuroligin co-culture recruitment assay in neurons","pmids":["22960622"],"confidence":"Medium","gaps":["Functional role at the synapse not addressed","Whether endogenous neuroligin-dependent recruitment is physiologically required was not tested"]},{"year":2014,"claim":"Discovery that the Syt11 C2A domain binds vti1a and the C2B domain binds RISC components (SND1, Ago2, FMRP) in β-cells hinted at dual trafficking and RNA-regulatory roles.","evidence":"Affinity purification/mass spectrometry, domain-specific pulldowns, direct binding assay in pancreatic β-cells","pmids":["24882364"],"confidence":"Medium","gaps":["Functional consequences of RISC interaction not established","Whether Syt11-RISC binding occurs in neurons is unknown"]},{"year":2016,"claim":"Placing SYT11 downstream of an ATP13A2–MYCBP2–TSC2–mTORC1–TFEB signaling axis, and showing that SYT11 depletion causes lysosomal dysfunction and impaired autophagosome degradation, established SYT11 as a node linking PD-associated genes to lysosomal homeostasis.","evidence":"siRNA knockdown, ubiquitination assays, mTORC1/TFEB pathway analysis, lysosomal function assays","pmids":["27278822"],"confidence":"High","gaps":["Direct mechanism by which Syt11 maintains lysosomal function not identified","Whether this pathway operates in dopaminergic neurons in vivo is unconfirmed"]},{"year":2017,"claim":"Demonstrating that Syt11 inhibits cytokine secretion and phagocytosis in microglia, localizing to the TGN and recycling endosomes and being recruited to phagosomes, expanded Syt11's role beyond neurons to innate immune regulation.","evidence":"siRNA knockdown and overexpression in primary microglia, cytokine ELISA, phagocytosis assays, NF-κB activation assays","pmids":["28686317"],"confidence":"High","gaps":["In vivo microglial phenotype of Syt11 loss not yet shown at this stage","Molecular mechanism linking Syt11 to NF-κB suppression not defined"]},{"year":2018,"claim":"Identifying Syt11 as a parkin substrate whose accumulation upon parkin deficiency impairs striatal dopamine release and causes dopaminergic neurodegeneration — reversible by SYT11 knockdown — directly linked Syt11 dosage to Parkinson's disease pathogenesis.","evidence":"Unilateral overexpression in SNpc, conditional KO, parkin-deficient mouse models, dopamine release measurements, motor behavior, immunoprecipitation","pmids":["29311685"],"confidence":"High","gaps":["Specific ubiquitination sites on Syt11 by parkin not mapped","Whether Syt11 accumulation is sufficient for human PD pathology is unresolved"]},{"year":2019,"claim":"Revealing that Syt11 resides on trafficking endosomes (not canonical synaptic vesicles) that undergo slow activity-dependent exocytosis, and that conditional forebrain KO impairs synaptic plasticity and memory without affecting fast neurotransmitter release, redefined Syt11 as a plasticity regulator operating through a non-canonical vesicle population.","evidence":"Constitutive and conditional KO mice, live imaging, mass spectrometry interactome, electrophysiology, behavioral assays","pmids":["30808661"],"confidence":"High","gaps":["Cargo of Syt11-positive endosomes not identified","Mechanism linking Syt11 vesicle cycling to long-term potentiation not resolved"]},{"year":2019,"claim":"Showing that Syt11 regulates caveolae-mediated endocytosis and osmotic stress response in astrocytes via direct interaction with cavin1 and EHD2 extended its trafficking-inhibitory function to a non-neuronal membrane domain.","evidence":"Syt11 KO astrocytes, live imaging, co-IP/pulldown, electron microscopy, osmotic stress assays","pmids":["31908017"],"confidence":"High","gaps":["Whether Syt11-caveolae regulation occurs in neurons or other cell types is unknown","Structural basis of Syt11–cavin1/EHD2 interaction not determined"]},{"year":2020,"claim":"Quantifying Syt11 as a short-lived protein (t½ ~1.5 h in neurons, ~0.6 h in astrocytes) degraded by the ubiquitin–proteasome pathway in a parkin-dependent manner in neurons established that its abundance is tightly controlled by activity-dependent proteolysis.","evidence":"Cycloheximide chase, proteasome inhibitors, parkin overexpression/knockdown in neurons and astrocytes","pmids":["32976921"],"confidence":"Medium","gaps":["Specific ubiquitin chain types and lysine residues on Syt11 not identified","Parkin-independent degradation mechanism in astrocytes not elucidated"]},{"year":2021,"claim":"Identifying vti1a as the direct C2A-domain binding partner through which Syt11 suppresses spontaneous neurotransmitter release — with genetic epistasis confirming vti1a as the principal target — resolved the molecular mechanism underlying Syt11's inhibitory role at the synapse.","evidence":"GST pulldown, co-IP, Syt11-KO neurons, mEPSC recordings, vti1a knockdown epistasis","pmids":["34599505"],"confidence":"High","gaps":["Structural detail of the Syt11 C2A–vti1a interface is lacking","Whether this mechanism operates at inhibitory synapses was not tested"]},{"year":2022,"claim":"Discovery that Syt11 co-localizes with insulin granules and that its knockdown increases both basal and glucose-stimulated insulin secretion extended its inhibitory secretory function to pancreatic β-cells.","evidence":"siRNA knockdown in INS-1 832/13 cells, ELISA, patch-clamp, confocal colocalization","pmids":["35753051"],"confidence":"Medium","gaps":["Mechanism by which Syt11 inhibits insulin secretion not determined","Single cell line study without in vivo validation"]},{"year":2022,"claim":"Identification of Syt11 as a scaffold bridging MKK7 and JNK1 to promote JNK/cJun signaling and EMT in gastric cancer revealed a non-canonical signaling scaffold function outside the nervous system.","evidence":"Phospho-kinase array, co-IP, xenograft and liver metastasis models, shRNA knockdown","pmids":["35768842"],"confidence":"Medium","gaps":["Whether Syt11-MKK7-JNK1 scaffolding is direct (all three simultaneously bound) not confirmed by reconstitution","Relevance to non-cancer cell types not explored"]},{"year":2023,"claim":"Mapping the Syt11 C2B domain interaction with endophilin A1 and demonstrating that a blocking peptide and EndoA1 knockdown reverse the accelerated endocytosis of Syt11-KO neurons identified the molecular basis of Syt11's brake on synaptic vesicle recycling.","evidence":"GST pulldown, co-IP, Syt11-KO neurons, EndoA1 epistasis, peptide competition, calyx of Held electrophysiology","pmids":["37474308"],"confidence":"High","gaps":["How Syt11 binding inhibits EndoA1's membrane-bending activity is structurally undefined","Whether the blocking peptide is therapeutically viable in vivo is untested"]},{"year":2023,"claim":"Demonstrating that palmitoylation at Cys39/40 stabilizes Syt11 on intracellular membranes and that the resulting increased Syt11 promotes α-synuclein monomerization uncovered a lipid-modification-dependent mechanism linking Syt11 accumulation to synucleinopathy.","evidence":"Acyl-RAC, site-directed mutagenesis of Cys39/40, biochemical fractionation, α-synuclein tetramer-to-monomer quantification in cortical neurons","pmids":["36787382"],"confidence":"High","gaps":["Palmitoyl-transferase(s) responsible for Syt11 palmitoylation not identified","In vivo contribution of palmitoylation to PD pathology not tested"]},{"year":2023,"claim":"In vivo microglia-specific conditional KO of Syt11 confirmed its role as an immune brake: loss enhanced phagocytosis of α-synuclein fibrils and elevated cytokine production, with vti1a/vti1b identified as linker-domain binding partners mediating this suppression.","evidence":"Inducible microglia-specific cKO, LPS and α-synuclein PD model in vivo, co-IP, competitive peptide assay","pmids":["37924268"],"confidence":"High","gaps":["How Syt11–vti1a/b interaction mechanistically suppresses NF-κB signaling is not resolved","Whether microglial Syt11 loss is neuroprotective or neurotoxic in long-term PD models is unknown"]},{"year":2024,"claim":"Showing that Syt11 bridges KCTD16, GABAB receptors, and Cav2.2 channels on post-Golgi vesicles and stabilizes them at the plasma membrane established a new role for Syt11 as a trafficking scaffold for presynaptic signaling complexes.","evidence":"Reciprocal co-IP, proximity ligation, Syt11 KO mouse electrophysiology, live imaging, biochemical fractionation","pmids":["38698221"],"confidence":"High","gaps":["Whether other Syt family members compensate for Syt11 in GABAB trafficking is unknown","Structural basis of Syt11–KCTD16 interaction not determined"]},{"year":2024,"claim":"Stage-specific conditional KO demonstrated that Syt11 loss in dopamine neurons during early adolescence (but not adulthood) causes persistent schizophrenia-like social deficits via dopamine over-transmission, revealing a critical developmental window.","evidence":"Developmental stage-specific conditional KO in dopamine neurons, electrophysiology, dopamine measurements, behavioral assays, mPFC structural analysis","pmids":["39632880"],"confidence":"High","gaps":["Molecular mechanism by which developmental dopamine excess permanently alters mPFC circuitry is unclear","Whether this maps onto human developmental schizophrenia trajectories is unresolved"]},{"year":2025,"claim":"Identification of VHL as a second E3 ligase that ubiquitinates and degrades Syt11, with downstream consequences for SPINK1 expression and gastric cancer cell growth, expanded the repertoire of Syt11 post-translational regulators beyond parkin.","evidence":"Co-IP, ubiquitination assay, MG132 rescue, cycloheximide chase, overexpression/knockdown in gastric cancer cells","pmids":["40576306"],"confidence":"Medium","gaps":["Whether VHL-mediated Syt11 degradation occurs in neurons or only in cancer contexts is untested","Ubiquitination sites on Syt11 by VHL not mapped"]},{"year":null,"claim":"Despite extensive functional characterization, the structural basis of Syt11's Ca²⁺-independent C2 domains, the identity of cargoes in Syt11-positive trafficking endosomes, and the palmitoyl-transferase(s) responsible for its stabilization remain unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of Syt11 C2 domains available","Cargo identity of Syt11-positive endosomal vesicles in neurons not defined","Palmitoyl-transferase(s) acting on Syt11 Cys39/40 not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,6,7,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,5,6,8,9,18]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,7,11]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,3,7]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,13]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,5,6,7,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,5,6,7,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,4,16,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]}],"complexes":[],"partners":["VTI1A","SH3GL2","KCTD16","CACNA1B","CAVIN1","EHD2","PRKN","VHL"],"other_free_text":[]},"mechanistic_narrative":"Synaptotagmin-11 (SYT11) is a Ca²⁺-independent membrane-trafficking protein that functions as an inhibitory regulator of vesicle exocytosis and endocytosis across multiple cell types. In neurons, Syt11 resides on trafficking endosome-like vesicles distinct from synaptic vesicles, suppresses spontaneous neurotransmitter release by binding the SNARE protein vti1a via its C2A domain, and inhibits synaptic vesicle endocytosis through direct C2B-domain interaction with endophilin A1; it also recruits GABAB receptors and Cav2.2 channels to post-Golgi vesicles via KCTD16, stabilizing these signaling complexes at the plasma membrane [PMID:30808661, PMID:34599505, PMID:37474308, PMID:38698221]. In microglia, Syt11 suppresses cytokine secretion and phagocytosis through vti1a/vti1b binding, and in astrocytes it regulates caveolae-mediated endocytosis via interaction with cavin1 and EHD2 [PMID:28686317, PMID:37924268, PMID:31908017]. Syt11 is a short-lived protein degraded by parkin- and VHL-mediated ubiquitin–proteasome pathways and stabilized by palmitoylation at Cys39/Cys40, which also promotes pathological α-synuclein monomerization; accumulation of Syt11 due to parkin loss-of-function impairs dopamine release and causes dopaminergic neurodegeneration relevant to Parkinson's disease, while its early developmental loss in dopamine neurons produces schizophrenia-like social deficits through dopamine over-transmission [PMID:29311685, PMID:36787382, PMID:32976921, PMID:39632880]."},"prefetch_data":{"uniprot":{"accession":"Q9BT88","full_name":"Synaptotagmin-11","aliases":["Synaptotagmin XI","SytXI"],"length_aa":431,"mass_kda":48.3,"function":"Synaptotagmin family member involved in vesicular and membrane trafficking which does not bind Ca(2+). Inhibits clathrin-mediated and bulk endocytosis, functions to ensure precision in vesicle retrieval. Plays an important role in dopamine transmission by regulating endocytosis and the vesicle-recycling process. Essential component of a neuronal vesicular trafficking pathway that differs from the synaptic vesicle trafficking pathway but is crucial for development and synaptic plasticity. In macrophages and microglia, inhibits the conventional cytokine secretion, of at least IL6 and TNF, and phagocytosis. In astrocytes, regulates lysosome exocytosis, mechanism required for the repair of injured astrocyte cell membrane (By similarity). Required for the ATP13A2-mediated regulation of the autophagy-lysosome pathway (PubMed:27278822)","subcellular_location":"Cytoplasmic vesicle membrane; Perikaryon; Golgi apparatus, trans-Golgi network membrane; Recycling endosome membrane; Lysosome membrane; Cytoplasmic vesicle, phagosome; Cell projection, axon; Cell projection, dendrite; Postsynaptic density; Recycling endosome membrane; Cytoplasmic vesicle, clathrin-coated vesicle membrane; Perikaryon","url":"https://www.uniprot.org/uniprotkb/Q9BT88/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SYT11","classification":"Not Classified","n_dependent_lines":17,"n_total_lines":1208,"dependency_fraction":0.014072847682119206},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SYT11","total_profiled":1310},"omim":[{"mim_id":"608741","title":"SYNAPTOTAGMIN 11; SYT11","url":"https://www.omim.org/entry/608741"},{"mim_id":"606436","title":"SYNAPTOTAGMIN 12; SYT12","url":"https://www.omim.org/entry/606436"},{"mim_id":"602544","title":"PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN","url":"https://www.omim.org/entry/602544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":227.7}],"url":"https://www.proteinatlas.org/search/SYT11"},"hgnc":{"alias_symbol":["KIAA0080","MGC10881","MGC17226","DKFZp781D015"],"prev_symbol":[]},"alphafold":{"accession":"Q9BT88","domains":[{"cath_id":"2.60.40.150","chopping":"160-282","consensus_level":"high","plddt":91.9118,"start":160,"end":282},{"cath_id":"2.60.40.150","chopping":"295-428","consensus_level":"high","plddt":92.464,"start":295,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BT88","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BT88-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BT88-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SYT11","jax_strain_url":"https://www.jax.org/strain/search?query=SYT11"},"sequence":{"accession":"Q9BT88","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BT88.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BT88/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BT88"}},"corpus_meta":[{"pmid":"27278822","id":"PMC_27278822","title":"The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27278822","citation_count":159,"is_preprint":false},{"pmid":"21812969","id":"PMC_21812969","title":"Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population.","date":"2011","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21812969","citation_count":137,"is_preprint":false},{"pmid":"7584044","id":"PMC_7584044","title":"Prediction of the coding sequences of unidentified human genes. 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Overexpression of full-length, but not C2B-truncated, Syt11 in dopaminergic neurons of the substantia nigra pars compacta impairs striatal dopamine release by inhibiting endocytosis and vesicle pool replenishment, causing dopaminergic neuron degeneration. Parkin deficiency leads to Syt11 accumulation and PD-like neurotoxicity, which is reversed by SYT11 knockdown or knockout in dopaminergic neurons.\",\n      \"method\": \"In vivo unilateral overexpression, conditional knockout, parkin-deficient mouse models, dopamine release measurements, motor behavior assays, immunoprecipitation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal in vivo and in vitro methods, genetic rescue experiments, replicated mechanistic link\",\n      \"pmids\": [\"29311685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATP13A2 depletion negatively regulates SYT11 at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by MYCBP2-induced ubiquitination of TSC2, leading to mTORC1 activation and decreased TFEB-mediated transcription of SYT11. Increased SYT11 protein turnover is regulated by its ubiquitination and degradation. Decreased SYT11 levels induce lysosomal dysfunction and impaired autophagosome degradation.\",\n      \"method\": \"siRNA knockdown, transcriptional assays, ubiquitination assays, lysosomal function assays, mTORC1/TFEB pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in a single rigorous study identifying the complete pathway\",\n      \"pmids\": [\"27278822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Syt11 resides on abundant vesicles resembling trafficking endosomes (distinct from synaptic vesicles) in neurons. These vesicles recycle via the plasma membrane in an activity-dependent manner with slow, desynchronized exocytosis. Constitutive Syt11 knockout mice die shortly after birth. Conditional knockout in excitatory forebrain neurons impairs synaptic plasticity and memory without affecting fast neurotransmitter or peptide secretion, but reduces long-term synaptic potentiation.\",\n      \"method\": \"Conditional and constitutive knockout mice, live imaging, mass spectrometry (Syt11 interactome), electrophysiology, behavioral assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — constitutive and conditional KO with multiple functional readouts, MS interactome, strong mechanistic conclusions\",\n      \"pmids\": [\"30808661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Syt11 inhibits cytokine secretion (IL-6, TNF-α) and phagocytosis in microglia. Syt11 localizes to the trans-Golgi network and recycling endosomes, and is recruited to phagosomes. Syt11 knockdown increases NF-κB activation and cytokine synthesis/secretion capacity, and enhances phagocytosis including of α-synuclein fibrils. Overexpression of Syt11 suppresses these functions.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, immunofluorescence localization, cytokine ELISA, phagocytosis assays, NF-κB activation assays\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, gain- and loss-of-function with rescue, subcellular localization tied to function\",\n      \"pmids\": [\"28686317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Syt11 is palmitoylated at Cys39 and Cys40 (adjacent to its transmembrane domain) in mouse and human brain tissue and cultured cortical neurons. This palmitoylation localizes Syt11 to digitonin-insoluble intracellular membranes and protects it from endolysosomal degradation. Palmitoylation-mediated increase in Syt11 abundance enhances α-synuclein binding to intracellular membranes, decreasing physiologic tetrameric α-synuclein and increasing aggregation-prone monomeric α-synuclein. A palmitoylation-deficient mutant does not replicate these effects.\",\n      \"method\": \"Palmitoylation assays (acyl-RAC), site-directed mutagenesis, biochemical fractionation, α-synuclein tetramer/monomer quantification in neurons, overexpression of WT vs palmitoylation-deficient mutant\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis, biochemical reconstitution, multiple orthogonal methods establishing palmitoylation site and functional consequences\",\n      \"pmids\": [\"36787382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Syt11 inhibits spontaneous neurotransmitter release by directly interacting with vti1a (a non-canonical SNARE protein that maintains spontaneous release). The C2A domain of Syt11 binds vti1a with high affinity. Syt11-KO hippocampal neurons show increased miniature EPSC frequency; vti1a knockdown reverses this phenotype, identifying vti1a as the main target.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, affinity purification, Syt11 knockout neurons, electrophysiology (mEPSC recording), vti1a knockdown epistasis\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding confirmed by multiple methods, epistasis experiment identifies vti1a as main target\",\n      \"pmids\": [\"34599505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Syt11 inhibits synaptic vesicle (SV) endocytosis through direct, Ca2+-independent binding to endophilin A1 (EndoA1) via the C2B domain of Syt11 and the N-terminus of EndoA1. Syt11-KO accelerates SV endocytosis and vesicle recycling. A peptide (aa 314-336) from Syt11 C2B blocks Syt11-EndoA1 binding in vitro and in vivo, inhibiting SV endocytosis. EndoA1 knockdown reverses the Syt11-KO phenotype, establishing EndoA1 as the main inhibitory target of Syt11 in SV endocytosis.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, Syt11-KO mouse neurons, EndoA1 knockdown epistasis, peptide competition assays, electrophysiology at calyx of Held, live imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding characterization with domain mapping, peptide inhibition, genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"37474308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Syt11 binds both the auxiliary GABAB receptor (GBR) subunit KCTD16 and Cav2.2 Ca2+ channels. Through these dual interactions, Syt11 recruits GBRs and Cav2.2 channels to post-Golgi vesicles, facilitating assembly of GBR/Cav2.2 signaling complexes. Syt11 also stabilizes GBRs and Cav2.2 at the neuronal plasma membrane by inhibiting constitutive internalization. Syt11-KO mice show deficits in presynaptic GBRs and Cav2.2, reduced neurotransmitter release, and decreased GBR-mediated presynaptic inhibition.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation, Syt11 KO mouse analysis, electrophysiology, live imaging, biochemical fractionation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, KO mouse with multiple functional readouts, multiple orthogonal methods\",\n      \"pmids\": [\"38698221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Syt11 regulates caveolae-mediated endocytosis and caveolar response to mechanical stimuli in astrocytes. Syt11-KO accelerates caveolae-mediated endocytosis, reduces caveolar structures on the cell surface, and impairs caveolar disassembly and astrocyte swelling during hypoosmotic stimuli. Syt11 directly interacts with cavin1 and EHD2 (but not caveolin-1), and its absence increases turnover of cavin1 and EHD2 and compromises membrane integrity. Live imaging showed Syt11 leaves caveolar structures before cavin1 during hypoosmotic stress.\",\n      \"method\": \"Syt11 KO astrocytes, live imaging, co-immunoprecipitation/pulldown, electron microscopy, osmotic stress assays, endocytosis assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined phenotype, direct binding identified, live imaging with functional consequence\",\n      \"pmids\": [\"31908017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Syt11 inhibits microglial immune responses in vivo. Inducible microglia-specific Syt11-cKO results in microglial activation and elevated cytokine mRNA. In a PD model, Syt11-cKO microglia show reduced migration to injection sites but enhanced phagocytosis of α-synuclein fibrils. Syt11 directly binds vti1a and vti1b via its linker domain; a competitive peptide derived from this domain induces cytokine secretion in WT microglia, phenocopying Syt11 KD.\",\n      \"method\": \"Inducible microglia-specific conditional KO, LPS and PD model in vivo, co-immunoprecipitation, peptide competition assay, cytokine measurements, phagocytosis assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with in vivo phenotype, direct binding with domain mapping and peptide inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"37924268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SYT11 functions as a scaffold protein in gastric cancer cells, binding both MKK7 and JNK1 to promote JNK1 phosphorylation. JNK activation leads to cJun activation and downstream expression of EMT-related genes (ANGPTL2, THBS4, Vimentin, JAM3). SYT11 knockdown reduces spheroid formation, tumor formation, and liver metastasis.\",\n      \"method\": \"Phospho-kinase array, co-immunoprecipitation, western blot, shRNA knockdown, mouse xenograft, liver metastasis model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP identifies complex, in vivo functional data, but single lab study\",\n      \"pmids\": [\"35768842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Impad1 interacts directly with Syt11 (a vesicle trafficking protein) to modulate Golgi apparatus morphology and vesicular trafficking. This interaction alters the extracellular matrix and tumor microenvironment to promote lung cancer invasion and metastasis. Inhibiting either Impad1 or Syt11 disrupts the cancer cell secretome and reverses invasive/metastatic phenotype.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays, in vitro and in vivo shRNA screens, Golgi morphology imaging, secretome analysis, invasion and metastasis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding interaction identified, functional KD with defined phenotype, but mechanistic detail is partial\",\n      \"pmids\": [\"36170810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Syt11 interacts with components of the RNA-induced silencing complex (RISC) in pancreatic β-cells. The C2A domain of Syt11 interacts with the Q-SNARE Vti1a, while the C2B domain interacts with SND1, Ago2, and FMRP (RISC components). Binding of C2B to SND1 was shown to be direct via SND1's N-terminal tandem repeats.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation, domain-specific pulldowns, direct binding assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding established for some interactions, but functional consequences of RISC interaction not fully characterized\",\n      \"pmids\": [\"24882364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Syt11 is expressed mainly in the brain and localizes to presynaptic neurotransmitter vesicles and plasma membrane (with some postsynaptic localization). Exogenously expressed Syt11 can form higher molecular weight complexes via its transmembrane domain. Syt11 is targeted to both dendrite and axon compartments, and is juxtaposed to postsynaptic markers in excitatory and inhibitory synapses. Both neuroligin-1 and neuroligin-2 recruit Syt11 in neuron co-culture.\",\n      \"method\": \"Immunocytochemistry, immunogold electron microscopy, subcellular fractionation, neuroligin recruitment assay, HEK293 expression\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization by electron microscopy, but limited functional consequence mapping\",\n      \"pmids\": [\"22960622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Transcriptional activity of the Syt11 gene is affected by the number of 33-bp repeats in its promoter region (containing an Sp1 binding site), with excessive expression associated with schizophrenia. A SNP in the 5'UTR region where YY1 can bind also affects transcriptional activity of Syt11.\",\n      \"method\": \"Reporter/transient transcription assays, gel mobility shift assay, genetic association\",\n      \"journal\": \"American journal of medical genetics. Part B, Neuropsychiatric genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assays establish promoter regulation, but functional consequence of altered expression is inferred\",\n      \"pmids\": [\"17192956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Non-CpG methylation in the promoter region of syt11 reduces the binding of an Sp family transcription factor, thereby reducing syt11 expression. Cytosine residues in the minus strand of the promoter are partially methylated, and artificial methylation of these sites reduces reporter gene expression.\",\n      \"method\": \"Gel mobility shift assay, transient transcription assay with artificially methylated promoter, sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter and gel shift assays directly link non-CpG methylation to reduced Sp1 binding and transcription\",\n      \"pmids\": [\"15777718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Syt11 is a short-lived protein degraded primarily by the ubiquitin-proteasome pathway (UPP) in neurons (half-life ~1.49 h). Degradation is accelerated under sustained neuronal activity in a parkin-dependent manner. In astrocytes, Syt11 has a faster turnover (half-life ~0.58 h) partially via UPP, but is degraded via a parkin-independent mechanism under both isoosmotic and hypoosmotic conditions.\",\n      \"method\": \"Cycloheximide chase, proteasome inhibitors, parkin overexpression/knockdown, neuronal activity manipulation, western blot\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical measurement of protein half-life, multiple conditions tested, parkin dependency established\",\n      \"pmids\": [\"32976921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Syt11 deficiency in dopamine neurons during early adolescence (but not in adults) leads to persistent social deficits and schizophrenia-like behaviors by mediating dopamine over-transmission. Dopamine neuron over-excitation before late adolescence induces persistent schizophrenia-associated behavioral deficits with structural and functional alterations in the mPFC. D2R-targeting interventions presynaptically or postsynaptically show therapeutic effects on social deficits.\",\n      \"method\": \"Conditional Syt11 knockout in dopamine neurons (developmental stage-specific), electrophysiology, dopamine measurements, behavioral assays, mPFC structural/functional analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with stage-specific manipulation, multiple functional readouts, mechanistic pathway established\",\n      \"pmids\": [\"39632880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Syt11 and Syt13 co-localize with insulin in insulin granules in β-cells. Downregulation of Syt11 in INS-1 832/13 cells increases basal and glucose-induced insulin secretion (suggesting an inhibitory role), without affecting exocytosis amplitude or Ca2+ currents. Downregulation of Syt13 decreases insulin secretion and abolishes forskolin-enhanced secretion.\",\n      \"method\": \"siRNA knockdown, ELISA, patch-clamp electrophysiology, confocal microscopy colocalization\",\n      \"journal\": \"Acta physiologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization and functional KD established, but mechanism of Syt11 inhibition of secretion not fully resolved\",\n      \"pmids\": [\"35753051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VHL (an E3 ubiquitin ligase) binds SYT11 protein and promotes its proteasomal degradation by ubiquitination. VHL overexpression decreases SYT11 protein (not mRNA) and shortens its half-life; MG132 (proteasome inhibitor) reverses this. VHL-mediated SYT11 degradation downregulates SPINK1, which in turn inhibits gastric cancer cell growth and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, MG132 rescue, cycloheximide chase, transcriptome sequencing, knockdown/overexpression functional assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by co-IP, ubiquitination assay establishes mechanism, but single lab study\",\n      \"pmids\": [\"40576306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compensatory upregulation of Syt11 in parkin knockout mice during the suckling stage (but not in adults) conceals PD-associated phenotypes. Parkin knockdown in adult SNpc impairs dopamine release and causes motor deficits. Overexpression of Syt11 alone induces PD-like motor and non-motor impairments, impaired dopamine release and reuptake.\",\n      \"method\": \"Parkin KO and KD mouse models, Syt11 overexpression in SNpc, dopamine release measurements, motor behavior assays, western blot\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mouse models and rescue experiments, but single lab study\",\n      \"pmids\": [\"39901263\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Synaptotagmin-11 (Syt11) is a Ca2+-independent vesicle-trafficking protein that acts as an inhibitory regulator of multiple membrane trafficking pathways: it suppresses spontaneous neurotransmitter release by binding vti1a via its C2A domain, inhibits synaptic vesicle endocytosis through direct interaction with endophilin A1 via its C2B domain, recruits GABAB receptors and Cav2.2 channels to post-Golgi vesicles via KCTD16 binding, inhibits cytokine secretion and phagocytosis in microglia via vti1a/vti1b interactions, and is regulated post-translationally as a substrate of parkin-mediated ubiquitination and by palmitoylation at Cys39/Cys40 (which protects it from endolysosomal degradation and promotes pathological α-synuclein monomerization); its accumulation due to parkin loss-of-function mediates dopaminergic neurotoxicity relevant to Parkinson's disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Synaptotagmin-11 (SYT11) is a Ca²⁺-independent membrane-trafficking protein that functions as an inhibitory regulator of vesicle exocytosis and endocytosis across multiple cell types. In neurons, Syt11 resides on trafficking endosome-like vesicles distinct from synaptic vesicles, suppresses spontaneous neurotransmitter release by binding the SNARE protein vti1a via its C2A domain, and inhibits synaptic vesicle endocytosis through direct C2B-domain interaction with endophilin A1; it also recruits GABAB receptors and Cav2.2 channels to post-Golgi vesicles via KCTD16, stabilizing these signaling complexes at the plasma membrane [PMID:30808661, PMID:34599505, PMID:37474308, PMID:38698221]. In microglia, Syt11 suppresses cytokine secretion and phagocytosis through vti1a/vti1b binding, and in astrocytes it regulates caveolae-mediated endocytosis via interaction with cavin1 and EHD2 [PMID:28686317, PMID:37924268, PMID:31908017]. Syt11 is a short-lived protein degraded by parkin- and VHL-mediated ubiquitin–proteasome pathways and stabilized by palmitoylation at Cys39/Cys40, which also promotes pathological α-synuclein monomerization; accumulation of Syt11 due to parkin loss-of-function impairs dopamine release and causes dopaminergic neurodegeneration relevant to Parkinson's disease, while its early developmental loss in dopamine neurons produces schizophrenia-like social deficits through dopamine over-transmission [PMID:29311685, PMID:36787382, PMID:32976921, PMID:39632880].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that non-CpG methylation within the SYT11 promoter reduces Sp-family transcription factor binding and transcription revealed an epigenetic layer controlling SYT11 expression levels.\",\n      \"evidence\": \"Gel shift and reporter assays with artificially methylated promoter constructs\",\n      \"pmids\": [\"15777718\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance of non-CpG methylation at endogenous SYT11 locus not demonstrated\",\n        \"No link to functional consequences of altered Syt11 protein levels\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification that variable 33-bp repeat number in the SYT11 promoter modulates transcription via Sp1 binding, with a YY1-dependent 5′UTR SNP also affecting expression, connected SYT11 dosage variation to schizophrenia risk.\",\n      \"evidence\": \"Reporter assays, gel shift assays, and genetic association in schizophrenia cohorts\",\n      \"pmids\": [\"17192956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of altered Syt11 expression in neurons not tested\",\n        \"Genetic association not replicated in independent cohorts within this study\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that Syt11 localizes to presynaptic vesicles and plasma membrane at both excitatory and inhibitory synapses, and is recruited by neuroligins, established its synaptic identity as a vesicle-associated protein.\",\n      \"evidence\": \"Immunogold electron microscopy, subcellular fractionation, neuroligin co-culture recruitment assay in neurons\",\n      \"pmids\": [\"22960622\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role at the synapse not addressed\",\n        \"Whether endogenous neuroligin-dependent recruitment is physiologically required was not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that the Syt11 C2A domain binds vti1a and the C2B domain binds RISC components (SND1, Ago2, FMRP) in β-cells hinted at dual trafficking and RNA-regulatory roles.\",\n      \"evidence\": \"Affinity purification/mass spectrometry, domain-specific pulldowns, direct binding assay in pancreatic β-cells\",\n      \"pmids\": [\"24882364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequences of RISC interaction not established\",\n        \"Whether Syt11-RISC binding occurs in neurons is unknown\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing SYT11 downstream of an ATP13A2–MYCBP2–TSC2–mTORC1–TFEB signaling axis, and showing that SYT11 depletion causes lysosomal dysfunction and impaired autophagosome degradation, established SYT11 as a node linking PD-associated genes to lysosomal homeostasis.\",\n      \"evidence\": \"siRNA knockdown, ubiquitination assays, mTORC1/TFEB pathway analysis, lysosomal function assays\",\n      \"pmids\": [\"27278822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct mechanism by which Syt11 maintains lysosomal function not identified\",\n        \"Whether this pathway operates in dopaminergic neurons in vivo is unconfirmed\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that Syt11 inhibits cytokine secretion and phagocytosis in microglia, localizing to the TGN and recycling endosomes and being recruited to phagosomes, expanded Syt11's role beyond neurons to innate immune regulation.\",\n      \"evidence\": \"siRNA knockdown and overexpression in primary microglia, cytokine ELISA, phagocytosis assays, NF-κB activation assays\",\n      \"pmids\": [\"28686317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo microglial phenotype of Syt11 loss not yet shown at this stage\",\n        \"Molecular mechanism linking Syt11 to NF-κB suppression not defined\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Syt11 as a parkin substrate whose accumulation upon parkin deficiency impairs striatal dopamine release and causes dopaminergic neurodegeneration — reversible by SYT11 knockdown — directly linked Syt11 dosage to Parkinson's disease pathogenesis.\",\n      \"evidence\": \"Unilateral overexpression in SNpc, conditional KO, parkin-deficient mouse models, dopamine release measurements, motor behavior, immunoprecipitation\",\n      \"pmids\": [\"29311685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific ubiquitination sites on Syt11 by parkin not mapped\",\n        \"Whether Syt11 accumulation is sufficient for human PD pathology is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealing that Syt11 resides on trafficking endosomes (not canonical synaptic vesicles) that undergo slow activity-dependent exocytosis, and that conditional forebrain KO impairs synaptic plasticity and memory without affecting fast neurotransmitter release, redefined Syt11 as a plasticity regulator operating through a non-canonical vesicle population.\",\n      \"evidence\": \"Constitutive and conditional KO mice, live imaging, mass spectrometry interactome, electrophysiology, behavioral assays\",\n      \"pmids\": [\"30808661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cargo of Syt11-positive endosomes not identified\",\n        \"Mechanism linking Syt11 vesicle cycling to long-term potentiation not resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that Syt11 regulates caveolae-mediated endocytosis and osmotic stress response in astrocytes via direct interaction with cavin1 and EHD2 extended its trafficking-inhibitory function to a non-neuronal membrane domain.\",\n      \"evidence\": \"Syt11 KO astrocytes, live imaging, co-IP/pulldown, electron microscopy, osmotic stress assays\",\n      \"pmids\": [\"31908017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Syt11-caveolae regulation occurs in neurons or other cell types is unknown\",\n        \"Structural basis of Syt11–cavin1/EHD2 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Quantifying Syt11 as a short-lived protein (t½ ~1.5 h in neurons, ~0.6 h in astrocytes) degraded by the ubiquitin–proteasome pathway in a parkin-dependent manner in neurons established that its abundance is tightly controlled by activity-dependent proteolysis.\",\n      \"evidence\": \"Cycloheximide chase, proteasome inhibitors, parkin overexpression/knockdown in neurons and astrocytes\",\n      \"pmids\": [\"32976921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ubiquitin chain types and lysine residues on Syt11 not identified\",\n        \"Parkin-independent degradation mechanism in astrocytes not elucidated\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying vti1a as the direct C2A-domain binding partner through which Syt11 suppresses spontaneous neurotransmitter release — with genetic epistasis confirming vti1a as the principal target — resolved the molecular mechanism underlying Syt11's inhibitory role at the synapse.\",\n      \"evidence\": \"GST pulldown, co-IP, Syt11-KO neurons, mEPSC recordings, vti1a knockdown epistasis\",\n      \"pmids\": [\"34599505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural detail of the Syt11 C2A–vti1a interface is lacking\",\n        \"Whether this mechanism operates at inhibitory synapses was not tested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that Syt11 co-localizes with insulin granules and that its knockdown increases both basal and glucose-stimulated insulin secretion extended its inhibitory secretory function to pancreatic β-cells.\",\n      \"evidence\": \"siRNA knockdown in INS-1 832/13 cells, ELISA, patch-clamp, confocal colocalization\",\n      \"pmids\": [\"35753051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which Syt11 inhibits insulin secretion not determined\",\n        \"Single cell line study without in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of Syt11 as a scaffold bridging MKK7 and JNK1 to promote JNK/cJun signaling and EMT in gastric cancer revealed a non-canonical signaling scaffold function outside the nervous system.\",\n      \"evidence\": \"Phospho-kinase array, co-IP, xenograft and liver metastasis models, shRNA knockdown\",\n      \"pmids\": [\"35768842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Syt11-MKK7-JNK1 scaffolding is direct (all three simultaneously bound) not confirmed by reconstitution\",\n        \"Relevance to non-cancer cell types not explored\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping the Syt11 C2B domain interaction with endophilin A1 and demonstrating that a blocking peptide and EndoA1 knockdown reverse the accelerated endocytosis of Syt11-KO neurons identified the molecular basis of Syt11's brake on synaptic vesicle recycling.\",\n      \"evidence\": \"GST pulldown, co-IP, Syt11-KO neurons, EndoA1 epistasis, peptide competition, calyx of Held electrophysiology\",\n      \"pmids\": [\"37474308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Syt11 binding inhibits EndoA1's membrane-bending activity is structurally undefined\",\n        \"Whether the blocking peptide is therapeutically viable in vivo is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that palmitoylation at Cys39/40 stabilizes Syt11 on intracellular membranes and that the resulting increased Syt11 promotes α-synuclein monomerization uncovered a lipid-modification-dependent mechanism linking Syt11 accumulation to synucleinopathy.\",\n      \"evidence\": \"Acyl-RAC, site-directed mutagenesis of Cys39/40, biochemical fractionation, α-synuclein tetramer-to-monomer quantification in cortical neurons\",\n      \"pmids\": [\"36787382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Palmitoyl-transferase(s) responsible for Syt11 palmitoylation not identified\",\n        \"In vivo contribution of palmitoylation to PD pathology not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In vivo microglia-specific conditional KO of Syt11 confirmed its role as an immune brake: loss enhanced phagocytosis of α-synuclein fibrils and elevated cytokine production, with vti1a/vti1b identified as linker-domain binding partners mediating this suppression.\",\n      \"evidence\": \"Inducible microglia-specific cKO, LPS and α-synuclein PD model in vivo, co-IP, competitive peptide assay\",\n      \"pmids\": [\"37924268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How Syt11–vti1a/b interaction mechanistically suppresses NF-κB signaling is not resolved\",\n        \"Whether microglial Syt11 loss is neuroprotective or neurotoxic in long-term PD models is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showing that Syt11 bridges KCTD16, GABAB receptors, and Cav2.2 channels on post-Golgi vesicles and stabilizes them at the plasma membrane established a new role for Syt11 as a trafficking scaffold for presynaptic signaling complexes.\",\n      \"evidence\": \"Reciprocal co-IP, proximity ligation, Syt11 KO mouse electrophysiology, live imaging, biochemical fractionation\",\n      \"pmids\": [\"38698221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other Syt family members compensate for Syt11 in GABAB trafficking is unknown\",\n        \"Structural basis of Syt11–KCTD16 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Stage-specific conditional KO demonstrated that Syt11 loss in dopamine neurons during early adolescence (but not adulthood) causes persistent schizophrenia-like social deficits via dopamine over-transmission, revealing a critical developmental window.\",\n      \"evidence\": \"Developmental stage-specific conditional KO in dopamine neurons, electrophysiology, dopamine measurements, behavioral assays, mPFC structural analysis\",\n      \"pmids\": [\"39632880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which developmental dopamine excess permanently alters mPFC circuitry is unclear\",\n        \"Whether this maps onto human developmental schizophrenia trajectories is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of VHL as a second E3 ligase that ubiquitinates and degrades Syt11, with downstream consequences for SPINK1 expression and gastric cancer cell growth, expanded the repertoire of Syt11 post-translational regulators beyond parkin.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, MG132 rescue, cycloheximide chase, overexpression/knockdown in gastric cancer cells\",\n      \"pmids\": [\"40576306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether VHL-mediated Syt11 degradation occurs in neurons or only in cancer contexts is untested\",\n        \"Ubiquitination sites on Syt11 by VHL not mapped\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive functional characterization, the structural basis of Syt11's Ca²⁺-independent C2 domains, the identity of cargoes in Syt11-positive trafficking endosomes, and the palmitoyl-transferase(s) responsible for its stabilization remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of Syt11 C2 domains available\",\n        \"Cargo identity of Syt11-positive endosomal vesicles in neurons not defined\",\n        \"Palmitoyl-transferase(s) acting on Syt11 Cys39/40 not identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6, 7, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 5, 6, 8, 9, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 7, 11]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 5, 6, 7, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 5, 6, 7, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 4, 16, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"VTI1A\",\n      \"SH3GL2\",\n      \"KCTD16\",\n      \"CACNA1B\",\n      \"CAVIN1\",\n      \"EHD2\",\n      \"PRKN\",\n      \"VHL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}