{"gene":"ESYT3","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"E-Syt3 localizes to the plasma membrane, with its C2C domain acting as the targeting motif that directs PM localization independently of the transmembrane region. The C2A domain mediates Ca2+-dependent phospholipid binding at micromolar Ca2+ concentrations.","method":"Transfection of myc-tagged constructs, structure/function mutagenesis, in vitro Ca2+-dependent phospholipid binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical binding assay plus domain-deletion mutagenesis with localization readout, replicated across E-Syt family members","pmids":["17360437"],"is_preprint":false},{"year":2013,"finding":"E-Syt3, along with E-Syt1 and E-Syt2, functions as an ER-resident tethering protein that bridges ER-plasma membrane contact sites via C2 domain-dependent interactions requiring PI(4,5)P2 (for E-Syt3 and E-Syt2). The E-Syts form heteromeric complexes, enabling cytosolic Ca2+ regulation of ER-PM contact formation. These contacts are distinct from STIM1/Orai1-mediated store-operated Ca2+ entry sites.","method":"Live-cell imaging, co-immunoprecipitation, PI(4,5)P2 depletion experiments, Ca2+ manipulation, epistasis with STIM1/Orai1 knockdown","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (imaging, Co-IP, lipid manipulation, genetic epistasis) in a highly cited study replicated across the field","pmids":["23791178"],"is_preprint":false},{"year":2015,"finding":"E-Syt3 and E-Syt2 (but not E-Syt1) selectively interact in vivo with activated FGFR1; the interaction is independent of receptor autophosphorylation but depends on receptor conformation. The E-Syts hetero- and homodimerize, with E-Syt2 homodimerization requiring a TM-adjacent sequence but not the SMP domain.","method":"Co-immunoprecipitation in transfected and activated receptor cells, domain-deletion mutagenesis, kinase-dead receptor constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with mutagenesis, single lab study","pmids":["25922075"],"is_preprint":false},{"year":2016,"finding":"Triple knockout of all three E-Syt isoforms (including E-Syt3) in mice produces viable and fertile animals without major ER dysfunction, indicating E-Syts are dispensable for basic cellular functions in unchallenged laboratory conditions. Knock-in mice with inactivating mutations in C2A Ca2+-binding sites of E-Syt1 and E-Syt2 are also normal.","method":"Constitutive and conditional triple knockout mice, knock-in point mutants at Ca2+-binding sites, histology, synaptic protein analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — rigorous genetic loss-of-function with multiple mutant alleles, replicated by independent lab (PMID 27399837)","pmids":["27348751","27399837"],"is_preprint":false},{"year":2014,"finding":"Loss of E-Syt2 and E-Syt3 together in mouse embryonic fibroblasts reduces cell migration and impairs resistance to oxidative stress in vitro, while esyt2−/−/esyt3−/− mice develop normally and are viable and fertile.","method":"Double knockout mouse generation, in vitro migration assays, oxidative stress survival assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — clean double KO with defined cellular phenotypes, single lab","pmids":["25486202"],"is_preprint":false},{"year":2017,"finding":"RASSF4 regulates the ER-PM tethering function of E-Syt2 and E-Syt3 through ARF6-dependent control of plasma membrane PI(4,5)P2 levels; RASSF4 knockdown reduces steady-state PM PI(4,5)P2, impairing E-Syt localization at ER-PM junctions.","method":"siRNA knockdown, PI(4,5)P2 biosensor imaging, Co-immunoprecipitation with ARF6, live-cell imaging of E-Syt2/3 at ER-PM junctions","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods, single lab, places E-Syt3 downstream of RASSF4/ARF6/PI(4,5)P2 axis","pmids":["28600435"],"is_preprint":false},{"year":2017,"finding":"E-Syt3 (along with E-Syt1) negatively modulates HSV-1 viral release, cell-to-cell spread, and viral entry — all membrane fusion events — and impairs virus-induced syncytia formation, suggesting E-Syt proteins act as negative regulators of viral fusion machinery.","method":"siRNA knockdown of E-Syt1/E-Syt3, viral plaque assays, cell-to-cell spread assays, syncytia formation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional knockdown with defined viral phenotypes, single lab","pmids":["29046455"],"is_preprint":false},{"year":2017,"finding":"Knockdown of ESYT3 (and family members ESYT1 and ESYT2) significantly decreases ANO1 (anoctamin 1) current density at the plasma membrane, indicating E-Syt3 contributes to ANO1 trafficking/function.","method":"siRNA knockdown, microscopy-based ANO1 traffic assay, electrophysiological current density measurement","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, combined knockdown of all three family members limits specificity to E-Syt3","pmids":["29154949"],"is_preprint":false},{"year":2020,"finding":"Hypothalamic E-Syt3 in POMC neurons promotes diet-induced obesity; its ablation increases POMC processing to α-MSH, increases protein kinase C and AP-1 activities, and upregulates prohormone convertase expression, leading to improved energy balance.","method":"Whole-body and POMC neuron-specific conditional knockout mice, metabolic phenotyping, POMC/α-MSH quantification, PKC activity assay, AP-1 reporter, prohormone convertase expression analysis, adeno-associated virus overexpression in arcuate nucleus","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO plus gain-of-function with multiple molecular readouts in a single rigorous study","pmids":["32747560"],"is_preprint":false},{"year":2021,"finding":"In differentiating adipocytes, E-Syt3's carboxyl C2C domain is proteolytically cleaved in a proteasome-dependent multi-step mechanism; the truncated E-Syt3ΔC2C localizes to a specialized ER cisterna (the 'primordial cisterna') that nucleates lipid droplet biogenesis. Knockdown of E-Syt3 inhibits lipid droplet biogenesis.","method":"Confocal and live-cell time-lapse imaging, electron microscopy, 3D electron tomography, proteasome inhibition, siRNA knockdown of E-Syt3, PLIN1 co-localization","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple imaging modalities plus loss-of-function with specific lipid droplet phenotype, single lab","pmids":["34693607"],"is_preprint":false},{"year":2024,"finding":"ESYT3 directly interacts with STING and activates the cGAS-STING signaling pathway in lung adenocarcinoma cells, leading to increased type I IFN production and downstream chemokines CCL5 and CXCL10, thereby enhancing radioimmune responses.","method":"Co-immunoprecipitation, immunofluorescence co-staining, ESYT3 overexpression/knockdown, cytokine/chemokine quantification, in vivo tumor models with radiotherapy","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP plus functional overexpression with defined downstream molecular readouts, single lab","pmids":["39103908"],"is_preprint":false},{"year":2025,"finding":"E-Syt3 functions as a lipid transfer protein at ER/PM junctions that removes phosphatidylserine (PtdSer) from junctional nanodomains; PtdSer depletion by E-Syt3 dissociates the cAMP signaling complex, preventing CFTR activation, and prevents NBCe1-B activation by IRBIT. The C2C domain restricts E-Syt3 to the PM and is essential for its function. E-Syt3 depletion in mice improves chloride flux and fluid secretion in salivary glands and pancreatic ducts. ORP5 antagonizes E-Syt3 by supplying PtdSer to junctions.","method":"Mouse E-Syt3 knockdown in vivo, reconstitution of PtdSer signaling with exogenous lipids, CFTR and NBCe1-B activity assays, domain-deletion mutants of E-Syt3, fluid secretion measurements in isolated organs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vivo knockout, lipid reconstitution, domain mutagenesis, and functional ion transport assays in a single rigorous study","pmids":["40425857"],"is_preprint":false}],"current_model":"ESYT3 (E-Syt3) is an ER-resident tethering protein that uses its C2 domains (particularly C2A for Ca2+/phospholipid binding and C2C for PM targeting) to form PI(4,5)P2-dependent ER-PM contact sites where it acts as a phosphatidylserine lipid transfer protein, thereby controlling the lipid composition of junctional nanodomains, regulating downstream ion transport (CFTR, NBCe1-B), modulating cGAS-STING signaling, participating in POMC neuron energy homeostasis, and supporting lipid droplet biogenesis in adipocytes through proteasome-dependent C2C domain cleavage."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of E-Syt3's domain architecture established that its C2C domain is a plasma membrane targeting module and that C2A binds phospholipids in a Ca²⁺-dependent manner, providing the first molecular framework for understanding E-Syt family membrane association.","evidence":"Myc-tagged domain deletion constructs with localization imaging and in vitro Ca²⁺-dependent phospholipid binding assays","pmids":["17360437"],"confidence":"High","gaps":["No lipid transfer activity demonstrated at this stage","Endogenous protein localization not assessed","Whether C2A Ca²⁺ binding is required for function in vivo unknown"]},{"year":2013,"claim":"E-Syt3 was established as an ER-resident tethering protein that bridges ER–PM contacts via PI(4,5)P2-dependent C2 domain interactions and forms heteromeric complexes with other E-Syts, resolving how E-Syts create a distinct class of ER–PM contact sites separate from STIM1/Orai1 junctions.","evidence":"Live-cell imaging, co-immunoprecipitation, PI(4,5)P2 depletion, Ca²⁺ manipulation, and epistasis with STIM1/Orai1 knockdown","pmids":["23791178"],"confidence":"High","gaps":["Lipid transfer function of SMP domain not yet shown","Physiological roles of E-Syt3-specific contacts unclear","Stoichiometry and structure of heteromeric complexes unresolved"]},{"year":2014,"claim":"Double knockout of E-Syt2 and E-Syt3 revealed that combined loss impairs cell migration and oxidative stress resistance in vitro while mice remain viable, suggesting context-dependent rather than housekeeping roles for these tethers.","evidence":"Esyt2/Esyt3 double knockout MEFs with migration and stress survival assays; double KO mice phenotyping","pmids":["25486202"],"confidence":"Medium","gaps":["Individual contribution of E-Syt3 versus E-Syt2 not separated","Mechanism linking ER–PM contacts to migration or stress resistance unknown","Challenged conditions (e.g., metabolic stress) not tested in vivo"]},{"year":2015,"claim":"Discovery that E-Syt3 selectively interacts with activated FGFR1 in a conformation-dependent, phosphorylation-independent manner raised the possibility that ER–PM contacts sense receptor tyrosine kinase signaling states.","evidence":"Co-immunoprecipitation with wild-type and kinase-dead FGFR1, domain-deletion mutagenesis","pmids":["25922075"],"confidence":"Medium","gaps":["Functional consequence of FGFR1–E-Syt3 interaction not determined","No reciprocal validation with endogenous proteins","Downstream signaling impact uncharacterized"]},{"year":2016,"claim":"Triple E-Syt knockout mice were viable and fertile, definitively showing that E-Syts including E-Syt3 are dispensable for basic ER function and development under standard laboratory conditions, pointing toward stress- or tissue-specific roles.","evidence":"Constitutive and conditional triple KO mice with histology and synaptic protein analysis; independently replicated","pmids":["27348751","27399837"],"confidence":"High","gaps":["Metabolic, immune, or other challenge conditions not systematically tested","Compensatory mechanisms by non-E-Syt tethers not explored"]},{"year":2017,"claim":"RASSF4 was identified as an upstream regulator of E-Syt3 ER–PM tethering through ARF6-dependent control of PM PI(4,5)P2 levels, placing E-Syt3 within a defined signaling hierarchy that governs contact site formation.","evidence":"siRNA knockdown of RASSF4, PI(4,5)P2 biosensor imaging, Co-IP with ARF6, live-cell imaging of E-Syt localization","pmids":["28600435"],"confidence":"Medium","gaps":["Direct physical interaction between RASSF4 and E-Syt3 not shown","Whether RASSF4 regulation is tissue-specific is unknown","Functional consequences downstream of altered E-Syt3 tethering not measured"]},{"year":2017,"claim":"E-Syt3 knockdown enhanced HSV-1 viral release and cell-to-cell spread, establishing an unexpected role for E-Syt3 as a negative regulator of membrane fusion events during viral infection.","evidence":"siRNA knockdown of E-Syt1/E-Syt3, viral plaque assays, syncytia formation assays","pmids":["29046455"],"confidence":"Medium","gaps":["E-Syt1 and E-Syt3 contributions not cleanly separated","Mechanism by which E-Syt3 inhibits membrane fusion unclear","Generalizability to other enveloped viruses untested"]},{"year":2020,"claim":"Conditional ablation of E-Syt3 in hypothalamic POMC neurons demonstrated that E-Syt3 promotes diet-induced obesity by suppressing POMC processing to α-MSH through PKC/AP-1/prohormone convertase pathways, establishing the first tissue-specific in vivo function for E-Syt3.","evidence":"POMC neuron-specific conditional KO mice, metabolic phenotyping, α-MSH quantification, PKC/AP-1 activity assays, AAV overexpression","pmids":["32747560"],"confidence":"High","gaps":["How ER–PM contact lipid composition controls PKC/AP-1 in POMC neurons not resolved","Whether lipid transfer activity is required for the metabolic phenotype unknown","Relevance to human obesity not established"]},{"year":2021,"claim":"Proteasome-dependent cleavage of E-Syt3's C2C domain during adipogenesis redirects the truncated protein to a primordial ER cisterna that nucleates lipid droplet biogenesis, revealing a regulated post-translational mechanism that converts a PM-tethered protein into an organelle biogenesis factor.","evidence":"Confocal and live-cell imaging, electron tomography, proteasome inhibition, siRNA knockdown with lipid droplet quantification","pmids":["34693607"],"confidence":"Medium","gaps":["Protease identity mediating C2C cleavage not identified","Whether lipid transfer activity of truncated E-Syt3 is required for droplet nucleation unknown","Confirmation in primary adipocytes or in vivo lacking"]},{"year":2024,"claim":"E-Syt3 was found to directly interact with STING and activate cGAS-STING signaling to enhance type I interferon and chemokine production, linking ER–PM contact site biology to innate immune activation in lung adenocarcinoma.","evidence":"Co-immunoprecipitation, immunofluorescence, ESYT3 overexpression/knockdown, cytokine quantification, in vivo tumor models with radiotherapy","pmids":["39103908"],"confidence":"Medium","gaps":["Mechanism by which E-Syt3 activates STING (lipid transfer vs. scaffolding) not determined","Whether this extends beyond lung adenocarcinoma untested","Structural basis of E-Syt3–STING interaction unknown"]},{"year":2025,"claim":"E-Syt3 was definitively shown to function as a phosphatidylserine lipid transfer protein that depletes PtdSer from ER–PM junctional nanodomains, thereby dissociating cAMP signaling complexes and preventing CFTR and NBCe1-B activation; ORP5 was identified as a functional antagonist resupplying PtdSer, establishing the lipid-transfer-to-ion-transport signaling axis as the core mechanism of E-Syt3.","evidence":"In vivo E-Syt3 KO mice, PtdSer reconstitution, CFTR and NBCe1-B activity assays, domain-deletion mutants, fluid secretion measurements in salivary glands and pancreatic ducts","pmids":["40425857"],"confidence":"High","gaps":["Crystal or cryo-EM structure of E-Syt3 SMP domain with PtdSer cargo not available","Whether PtdSer transfer explains POMC neuron or STING phenotypes unknown","Relative contribution of E-Syt3 versus other SMP-domain lipid transfer proteins in vivo unresolved"]},{"year":null,"claim":"Key open questions include the structural basis of E-Syt3's lipid transfer selectivity, the identity of the protease cleaving C2C during adipogenesis, whether PtdSer depletion at ER–PM contacts is the unifying mechanism behind E-Syt3's diverse tissue-specific phenotypes, and whether E-Syt3 mutations contribute to human metabolic or secretory disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of SMP domain–lipid complex","Protease identity for C2C cleavage unknown","Unifying mechanism linking lipid transfer to all reported phenotypes not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,11]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[11]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,9,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,9]}],"complexes":["E-Syt heteromeric complex (E-Syt1/E-Syt2/E-Syt3)"],"partners":["ESYT1","ESYT2","FGFR1","STING1","ORP5"],"other_free_text":[]},"mechanistic_narrative":"ESYT3 (E-Syt3) is an ER-anchored membrane tethering and lipid transfer protein that forms PI(4,5)P2-dependent ER–plasma membrane contact sites, where it controls the phosphatidylserine composition of junctional nanodomains to regulate downstream ion transport and signaling. Its C2C domain targets the protein to the plasma membrane while its SMP domain transfers phosphatidylserine away from ER–PM junctions, thereby dissociating cAMP signaling complexes required for CFTR and NBCe1-B activation; ORP5 antagonizes this activity by resupplying phosphatidylserine [PMID:40425857, PMID:23791178, PMID:17360437]. Beyond ion channel regulation, E-Syt3 participates in lipid droplet biogenesis through proteasome-dependent C2C cleavage that redirects truncated E-Syt3 to a primordial ER cisterna nucleating droplets in adipocytes [PMID:34693607], modulates POMC neuron energy homeostasis where its ablation enhances α-MSH production and protects against diet-induced obesity [PMID:32747560], and activates cGAS-STING innate immune signaling through direct STING interaction [PMID:39103908]. Triple knockout of all E-Syt family members in mice yields viable, fertile animals under unchallenged conditions, indicating functional redundancy or context-dependent essentiality [PMID:27348751]."},"prefetch_data":{"uniprot":{"accession":"A0FGR9","full_name":"Extended synaptotagmin-3","aliases":["Chr3Syt"],"length_aa":886,"mass_kda":100.0,"function":"Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport (By similarity). Tethers the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/A0FGR9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESYT3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ESYT3","total_profiled":1310},"omim":[{"mim_id":"616692","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 3; ESYT3","url":"https://www.omim.org/entry/616692"},{"mim_id":"616691","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 2; ESYT2","url":"https://www.omim.org/entry/616691"},{"mim_id":"616670","title":"EXTENDED SYNAPTOTAGMIN-LIKE PROTEIN 1; ESYT1","url":"https://www.omim.org/entry/616670"},{"mim_id":"610841","title":"STROMAL INTERACTION MOLECULE 2; STIM2","url":"https://www.omim.org/entry/610841"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.2},{"tissue":"lung","ntpm":4.4},{"tissue":"skin 1","ntpm":6.1}],"url":"https://www.proteinatlas.org/search/ESYT3"},"hgnc":{"alias_symbol":["CHR3SYT"],"prev_symbol":["FAM62C"]},"alphafold":{"accession":"A0FGR9","domains":[{"cath_id":"2.60.40.150","chopping":"307-429","consensus_level":"high","plddt":87.1282,"start":307,"end":429},{"cath_id":"2.60.40.150","chopping":"445-462_485-585","consensus_level":"high","plddt":87.1669,"start":445,"end":585},{"cath_id":"2.60.40.150","chopping":"754-879","consensus_level":"high","plddt":84.9913,"start":754,"end":879},{"cath_id":"3.15.10","chopping":"120-301","consensus_level":"high","plddt":83.0314,"start":120,"end":301}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0FGR9","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0FGR9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0FGR9-F1-predicted_aligned_error_v6.png","plddt_mean":71.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESYT3","jax_strain_url":"https://www.jax.org/strain/search?query=ESYT3"},"sequence":{"accession":"A0FGR9","fasta_url":"https://rest.uniprot.org/uniprotkb/A0FGR9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0FGR9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0FGR9"}},"corpus_meta":[{"pmid":"23791178","id":"PMC_23791178","title":"PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/23791178","citation_count":476,"is_preprint":false},{"pmid":"17360437","id":"PMC_17360437","title":"E-Syts, a family of membranous Ca2+-sensor proteins with multiple C2 domains.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17360437","citation_count":156,"is_preprint":false},{"pmid":"16778180","id":"PMC_16778180","title":"Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16778180","citation_count":150,"is_preprint":false},{"pmid":"20484983","id":"PMC_20484983","title":"Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact.","date":"2010","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20484983","citation_count":89,"is_preprint":false},{"pmid":"28600435","id":"PMC_28600435","title":"RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P2.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/28600435","citation_count":57,"is_preprint":false},{"pmid":"27348751","id":"PMC_27348751","title":"Extended Synaptotagmin (ESyt) Triple Knock-Out Mice Are Viable and Fertile without Obvious Endoplasmic Reticulum Dysfunction.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27348751","citation_count":50,"is_preprint":false},{"pmid":"27399837","id":"PMC_27399837","title":"Loss of all 3 Extended Synaptotagmins does not affect normal mouse development, viability or fertility.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27399837","citation_count":34,"is_preprint":false},{"pmid":"29154949","id":"PMC_29154949","title":"A novel microscopy-based assay identifies extended synaptotagmin-1 (ESYT1) as a positive regulator of anoctamin 1 traffic.","date":"2017","source":"Biochimica et biophysica acta. 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Hypoplasia.","date":"2025","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/40923693","citation_count":0,"is_preprint":false},{"pmid":"40585125","id":"PMC_40585125","title":"Genome-Wide Insights into the Genes and Pathways Shaping Human Foveal Development.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40585125","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12286,"output_tokens":3147,"usd":0.042031},"stage2":{"model":"claude-opus-4-6","input_tokens":6522,"output_tokens":3324,"usd":0.173565},"total_usd":0.215596,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"E-Syt3 localizes to the plasma membrane, with its C2C domain acting as the targeting motif that directs PM localization independently of the transmembrane region. The C2A domain mediates Ca2+-dependent phospholipid binding at micromolar Ca2+ concentrations.\",\n      \"method\": \"Transfection of myc-tagged constructs, structure/function mutagenesis, in vitro Ca2+-dependent phospholipid binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical binding assay plus domain-deletion mutagenesis with localization readout, replicated across E-Syt family members\",\n      \"pmids\": [\"17360437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"E-Syt3, along with E-Syt1 and E-Syt2, functions as an ER-resident tethering protein that bridges ER-plasma membrane contact sites via C2 domain-dependent interactions requiring PI(4,5)P2 (for E-Syt3 and E-Syt2). The E-Syts form heteromeric complexes, enabling cytosolic Ca2+ regulation of ER-PM contact formation. These contacts are distinct from STIM1/Orai1-mediated store-operated Ca2+ entry sites.\",\n      \"method\": \"Live-cell imaging, co-immunoprecipitation, PI(4,5)P2 depletion experiments, Ca2+ manipulation, epistasis with STIM1/Orai1 knockdown\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (imaging, Co-IP, lipid manipulation, genetic epistasis) in a highly cited study replicated across the field\",\n      \"pmids\": [\"23791178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"E-Syt3 and E-Syt2 (but not E-Syt1) selectively interact in vivo with activated FGFR1; the interaction is independent of receptor autophosphorylation but depends on receptor conformation. The E-Syts hetero- and homodimerize, with E-Syt2 homodimerization requiring a TM-adjacent sequence but not the SMP domain.\",\n      \"method\": \"Co-immunoprecipitation in transfected and activated receptor cells, domain-deletion mutagenesis, kinase-dead receptor constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with mutagenesis, single lab study\",\n      \"pmids\": [\"25922075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Triple knockout of all three E-Syt isoforms (including E-Syt3) in mice produces viable and fertile animals without major ER dysfunction, indicating E-Syts are dispensable for basic cellular functions in unchallenged laboratory conditions. Knock-in mice with inactivating mutations in C2A Ca2+-binding sites of E-Syt1 and E-Syt2 are also normal.\",\n      \"method\": \"Constitutive and conditional triple knockout mice, knock-in point mutants at Ca2+-binding sites, histology, synaptic protein analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous genetic loss-of-function with multiple mutant alleles, replicated by independent lab (PMID 27399837)\",\n      \"pmids\": [\"27348751\", \"27399837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of E-Syt2 and E-Syt3 together in mouse embryonic fibroblasts reduces cell migration and impairs resistance to oxidative stress in vitro, while esyt2−/−/esyt3−/− mice develop normally and are viable and fertile.\",\n      \"method\": \"Double knockout mouse generation, in vitro migration assays, oxidative stress survival assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean double KO with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"25486202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RASSF4 regulates the ER-PM tethering function of E-Syt2 and E-Syt3 through ARF6-dependent control of plasma membrane PI(4,5)P2 levels; RASSF4 knockdown reduces steady-state PM PI(4,5)P2, impairing E-Syt localization at ER-PM junctions.\",\n      \"method\": \"siRNA knockdown, PI(4,5)P2 biosensor imaging, Co-immunoprecipitation with ARF6, live-cell imaging of E-Syt2/3 at ER-PM junctions\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, single lab, places E-Syt3 downstream of RASSF4/ARF6/PI(4,5)P2 axis\",\n      \"pmids\": [\"28600435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"E-Syt3 (along with E-Syt1) negatively modulates HSV-1 viral release, cell-to-cell spread, and viral entry — all membrane fusion events — and impairs virus-induced syncytia formation, suggesting E-Syt proteins act as negative regulators of viral fusion machinery.\",\n      \"method\": \"siRNA knockdown of E-Syt1/E-Syt3, viral plaque assays, cell-to-cell spread assays, syncytia formation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional knockdown with defined viral phenotypes, single lab\",\n      \"pmids\": [\"29046455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of ESYT3 (and family members ESYT1 and ESYT2) significantly decreases ANO1 (anoctamin 1) current density at the plasma membrane, indicating E-Syt3 contributes to ANO1 trafficking/function.\",\n      \"method\": \"siRNA knockdown, microscopy-based ANO1 traffic assay, electrophysiological current density measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, combined knockdown of all three family members limits specificity to E-Syt3\",\n      \"pmids\": [\"29154949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hypothalamic E-Syt3 in POMC neurons promotes diet-induced obesity; its ablation increases POMC processing to α-MSH, increases protein kinase C and AP-1 activities, and upregulates prohormone convertase expression, leading to improved energy balance.\",\n      \"method\": \"Whole-body and POMC neuron-specific conditional knockout mice, metabolic phenotyping, POMC/α-MSH quantification, PKC activity assay, AP-1 reporter, prohormone convertase expression analysis, adeno-associated virus overexpression in arcuate nucleus\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO plus gain-of-function with multiple molecular readouts in a single rigorous study\",\n      \"pmids\": [\"32747560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In differentiating adipocytes, E-Syt3's carboxyl C2C domain is proteolytically cleaved in a proteasome-dependent multi-step mechanism; the truncated E-Syt3ΔC2C localizes to a specialized ER cisterna (the 'primordial cisterna') that nucleates lipid droplet biogenesis. Knockdown of E-Syt3 inhibits lipid droplet biogenesis.\",\n      \"method\": \"Confocal and live-cell time-lapse imaging, electron microscopy, 3D electron tomography, proteasome inhibition, siRNA knockdown of E-Syt3, PLIN1 co-localization\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities plus loss-of-function with specific lipid droplet phenotype, single lab\",\n      \"pmids\": [\"34693607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ESYT3 directly interacts with STING and activates the cGAS-STING signaling pathway in lung adenocarcinoma cells, leading to increased type I IFN production and downstream chemokines CCL5 and CXCL10, thereby enhancing radioimmune responses.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-staining, ESYT3 overexpression/knockdown, cytokine/chemokine quantification, in vivo tumor models with radiotherapy\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional overexpression with defined downstream molecular readouts, single lab\",\n      \"pmids\": [\"39103908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"E-Syt3 functions as a lipid transfer protein at ER/PM junctions that removes phosphatidylserine (PtdSer) from junctional nanodomains; PtdSer depletion by E-Syt3 dissociates the cAMP signaling complex, preventing CFTR activation, and prevents NBCe1-B activation by IRBIT. The C2C domain restricts E-Syt3 to the PM and is essential for its function. E-Syt3 depletion in mice improves chloride flux and fluid secretion in salivary glands and pancreatic ducts. ORP5 antagonizes E-Syt3 by supplying PtdSer to junctions.\",\n      \"method\": \"Mouse E-Syt3 knockdown in vivo, reconstitution of PtdSer signaling with exogenous lipids, CFTR and NBCe1-B activity assays, domain-deletion mutants of E-Syt3, fluid secretion measurements in isolated organs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vivo knockout, lipid reconstitution, domain mutagenesis, and functional ion transport assays in a single rigorous study\",\n      \"pmids\": [\"40425857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESYT3 (E-Syt3) is an ER-resident tethering protein that uses its C2 domains (particularly C2A for Ca2+/phospholipid binding and C2C for PM targeting) to form PI(4,5)P2-dependent ER-PM contact sites where it acts as a phosphatidylserine lipid transfer protein, thereby controlling the lipid composition of junctional nanodomains, regulating downstream ion transport (CFTR, NBCe1-B), modulating cGAS-STING signaling, participating in POMC neuron energy homeostasis, and supporting lipid droplet biogenesis in adipocytes through proteasome-dependent C2C domain cleavage.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ESYT3 (E-Syt3) is an ER-anchored membrane tethering and lipid transfer protein that forms PI(4,5)P2-dependent ER–plasma membrane contact sites, where it controls the phosphatidylserine composition of junctional nanodomains to regulate downstream ion transport and signaling. Its C2C domain targets the protein to the plasma membrane while its SMP domain transfers phosphatidylserine away from ER–PM junctions, thereby dissociating cAMP signaling complexes required for CFTR and NBCe1-B activation; ORP5 antagonizes this activity by resupplying phosphatidylserine [PMID:40425857, PMID:23791178, PMID:17360437]. Beyond ion channel regulation, E-Syt3 participates in lipid droplet biogenesis through proteasome-dependent C2C cleavage that redirects truncated E-Syt3 to a primordial ER cisterna nucleating droplets in adipocytes [PMID:34693607], modulates POMC neuron energy homeostasis where its ablation enhances α-MSH production and protects against diet-induced obesity [PMID:32747560], and activates cGAS-STING innate immune signaling through direct STING interaction [PMID:39103908]. Triple knockout of all E-Syt family members in mice yields viable, fertile animals under unchallenged conditions, indicating functional redundancy or context-dependent essentiality [PMID:27348751].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of E-Syt3's domain architecture established that its C2C domain is a plasma membrane targeting module and that C2A binds phospholipids in a Ca²⁺-dependent manner, providing the first molecular framework for understanding E-Syt family membrane association.\",\n      \"evidence\": \"Myc-tagged domain deletion constructs with localization imaging and in vitro Ca²⁺-dependent phospholipid binding assays\",\n      \"pmids\": [\"17360437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No lipid transfer activity demonstrated at this stage\", \"Endogenous protein localization not assessed\", \"Whether C2A Ca²⁺ binding is required for function in vivo unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"E-Syt3 was established as an ER-resident tethering protein that bridges ER–PM contacts via PI(4,5)P2-dependent C2 domain interactions and forms heteromeric complexes with other E-Syts, resolving how E-Syts create a distinct class of ER–PM contact sites separate from STIM1/Orai1 junctions.\",\n      \"evidence\": \"Live-cell imaging, co-immunoprecipitation, PI(4,5)P2 depletion, Ca²⁺ manipulation, and epistasis with STIM1/Orai1 knockdown\",\n      \"pmids\": [\"23791178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid transfer function of SMP domain not yet shown\", \"Physiological roles of E-Syt3-specific contacts unclear\", \"Stoichiometry and structure of heteromeric complexes unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Double knockout of E-Syt2 and E-Syt3 revealed that combined loss impairs cell migration and oxidative stress resistance in vitro while mice remain viable, suggesting context-dependent rather than housekeeping roles for these tethers.\",\n      \"evidence\": \"Esyt2/Esyt3 double knockout MEFs with migration and stress survival assays; double KO mice phenotyping\",\n      \"pmids\": [\"25486202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual contribution of E-Syt3 versus E-Syt2 not separated\", \"Mechanism linking ER–PM contacts to migration or stress resistance unknown\", \"Challenged conditions (e.g., metabolic stress) not tested in vivo\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that E-Syt3 selectively interacts with activated FGFR1 in a conformation-dependent, phosphorylation-independent manner raised the possibility that ER–PM contacts sense receptor tyrosine kinase signaling states.\",\n      \"evidence\": \"Co-immunoprecipitation with wild-type and kinase-dead FGFR1, domain-deletion mutagenesis\",\n      \"pmids\": [\"25922075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FGFR1–E-Syt3 interaction not determined\", \"No reciprocal validation with endogenous proteins\", \"Downstream signaling impact uncharacterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Triple E-Syt knockout mice were viable and fertile, definitively showing that E-Syts including E-Syt3 are dispensable for basic ER function and development under standard laboratory conditions, pointing toward stress- or tissue-specific roles.\",\n      \"evidence\": \"Constitutive and conditional triple KO mice with histology and synaptic protein analysis; independently replicated\",\n      \"pmids\": [\"27348751\", \"27399837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolic, immune, or other challenge conditions not systematically tested\", \"Compensatory mechanisms by non-E-Syt tethers not explored\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"RASSF4 was identified as an upstream regulator of E-Syt3 ER–PM tethering through ARF6-dependent control of PM PI(4,5)P2 levels, placing E-Syt3 within a defined signaling hierarchy that governs contact site formation.\",\n      \"evidence\": \"siRNA knockdown of RASSF4, PI(4,5)P2 biosensor imaging, Co-IP with ARF6, live-cell imaging of E-Syt localization\",\n      \"pmids\": [\"28600435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between RASSF4 and E-Syt3 not shown\", \"Whether RASSF4 regulation is tissue-specific is unknown\", \"Functional consequences downstream of altered E-Syt3 tethering not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"E-Syt3 knockdown enhanced HSV-1 viral release and cell-to-cell spread, establishing an unexpected role for E-Syt3 as a negative regulator of membrane fusion events during viral infection.\",\n      \"evidence\": \"siRNA knockdown of E-Syt1/E-Syt3, viral plaque assays, syncytia formation assays\",\n      \"pmids\": [\"29046455\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E-Syt1 and E-Syt3 contributions not cleanly separated\", \"Mechanism by which E-Syt3 inhibits membrane fusion unclear\", \"Generalizability to other enveloped viruses untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional ablation of E-Syt3 in hypothalamic POMC neurons demonstrated that E-Syt3 promotes diet-induced obesity by suppressing POMC processing to α-MSH through PKC/AP-1/prohormone convertase pathways, establishing the first tissue-specific in vivo function for E-Syt3.\",\n      \"evidence\": \"POMC neuron-specific conditional KO mice, metabolic phenotyping, α-MSH quantification, PKC/AP-1 activity assays, AAV overexpression\",\n      \"pmids\": [\"32747560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ER–PM contact lipid composition controls PKC/AP-1 in POMC neurons not resolved\", \"Whether lipid transfer activity is required for the metabolic phenotype unknown\", \"Relevance to human obesity not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Proteasome-dependent cleavage of E-Syt3's C2C domain during adipogenesis redirects the truncated protein to a primordial ER cisterna that nucleates lipid droplet biogenesis, revealing a regulated post-translational mechanism that converts a PM-tethered protein into an organelle biogenesis factor.\",\n      \"evidence\": \"Confocal and live-cell imaging, electron tomography, proteasome inhibition, siRNA knockdown with lipid droplet quantification\",\n      \"pmids\": [\"34693607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protease identity mediating C2C cleavage not identified\", \"Whether lipid transfer activity of truncated E-Syt3 is required for droplet nucleation unknown\", \"Confirmation in primary adipocytes or in vivo lacking\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"E-Syt3 was found to directly interact with STING and activate cGAS-STING signaling to enhance type I interferon and chemokine production, linking ER–PM contact site biology to innate immune activation in lung adenocarcinoma.\",\n      \"evidence\": \"Co-immunoprecipitation, immunofluorescence, ESYT3 overexpression/knockdown, cytokine quantification, in vivo tumor models with radiotherapy\",\n      \"pmids\": [\"39103908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which E-Syt3 activates STING (lipid transfer vs. scaffolding) not determined\", \"Whether this extends beyond lung adenocarcinoma untested\", \"Structural basis of E-Syt3–STING interaction unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"E-Syt3 was definitively shown to function as a phosphatidylserine lipid transfer protein that depletes PtdSer from ER–PM junctional nanodomains, thereby dissociating cAMP signaling complexes and preventing CFTR and NBCe1-B activation; ORP5 was identified as a functional antagonist resupplying PtdSer, establishing the lipid-transfer-to-ion-transport signaling axis as the core mechanism of E-Syt3.\",\n      \"evidence\": \"In vivo E-Syt3 KO mice, PtdSer reconstitution, CFTR and NBCe1-B activity assays, domain-deletion mutants, fluid secretion measurements in salivary glands and pancreatic ducts\",\n      \"pmids\": [\"40425857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal or cryo-EM structure of E-Syt3 SMP domain with PtdSer cargo not available\", \"Whether PtdSer transfer explains POMC neuron or STING phenotypes unknown\", \"Relative contribution of E-Syt3 versus other SMP-domain lipid transfer proteins in vivo unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of E-Syt3's lipid transfer selectivity, the identity of the protease cleaving C2C during adipogenesis, whether PtdSer depletion at ER–PM contacts is the unifying mechanism behind E-Syt3's diverse tissue-specific phenotypes, and whether E-Syt3 mutations contribute to human metabolic or secretory disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SMP domain–lipid complex\", \"Protease identity for C2C cleavage unknown\", \"Unifying mechanism linking lipid transfer to all reported phenotypes not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 9, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0382551\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\n      \"E-Syt heteromeric complex (E-Syt1/E-Syt2/E-Syt3)\"\n    ],\n    \"partners\": [\n      \"ESYT1\",\n      \"ESYT2\",\n      \"FGFR1\",\n      \"STING1\",\n      \"ORP5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}