{"gene":"ERC2","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2012,"finding":"CAST/ERC2 directly interacts with the VDCC β4-subunit (and more weakly with the α1-subunit II-III linker) at presynaptic active zones; co-immunoprecipitation from mouse brain and pull-down assays confirmed this interaction. Coexpression of CAST and VDCCs in BHK cells shifted voltage dependence of VDCC activation toward the hyperpolarizing direction, indicating that the interaction functionally modulates Ca2+ channel gating.","method":"Co-immunoprecipitation from mouse brain, pull-down assay, heterologous coexpression with electrophysiology","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal co-IP from native tissue, direct pull-down mapping domains, and functional electrophysiology readout in single focused study","pmids":["22577167"],"is_preprint":false},{"year":2011,"finding":"P/Q- and N-type VDCCs act as scaffolding proteins that anchor CAST/ERC2 (together with Bassoon and Piccolo) to the presynaptic active zone membrane. Double knockout of P/Q- and N-type VDCCs in mice reduced the number of active zones, docked vesicles, and active-zone protein levels including CAST/ERC2. Direct interaction between VDCC β-subunits (β1b or β4) and CAST/ERC2 was confirmed by immunoprecipitation.","method":"Double knockout mouse model, immunoprecipitation, quantitative electron microscopy of active zones","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with defined ultrastructural phenotype plus confirmatory co-IP; replicated the CAST–β-subunit interaction found independently by Kiyonaka et al.","pmids":["21228161"],"is_preprint":false},{"year":2006,"finding":"ERC2/CAST1 interacts with the tandem PDZ protein syntenin-1 via a PDZ interaction involving the C-terminal region of ERC2. This interaction, together with multimerization of both ERC2 and syntenin-1, promotes the localization of syntenin-1 at presynaptic ERC2 clusters, thereby contributing to molecular organization of the presynaptic active zone.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization in neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal binding assays with domain mapping plus colocalization, single lab","pmids":["16421316"],"is_preprint":false},{"year":2019,"finding":"SRPK2 physically interacts with CAST1/ERC2 and phosphorylates it to regulate its self-assembly. Overexpression of SRPK2 in HEK293T, SH-SY5Y, and HT-22 cells modulated CAST1/ERC2 self-assembly (coiled-coil CC1 and CC4 domains involved). SRPK2 was detected in brain synaptic fractions, consistent with a synaptic role in controlling the level of CAST1/ERC2 oligomerization during presynaptic active-zone assembly.","method":"Co-immunoprecipitation in HEK293T and SH-SY5Y cells, overexpression/dominant-negative approach, synaptosomal fractionation","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP in multiple cell lines with domain mapping, synaptic fractionation, single lab","pmids":["31671734"],"is_preprint":false},{"year":2021,"finding":"A somatic missense mutation ERC2 L309I was identified in a patient with Maffucci's syndrome; in vitro experiments showed this mutation enhances angiogenesis, implicating ERC2 in a role that promotes hypervascularization when mutated.","method":"Exome sequencing, PCR confirmation, in vitro angiogenesis assay with mutant construct","journal":"Frontiers in endocrinology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single case, in vitro assay with limited mechanistic detail in abstract, single lab","pmids":["34790172"],"is_preprint":false}],"current_model":"ERC2/CAST1 is a presynaptic active-zone scaffolding protein that forms a cytomatrix complex with Bassoon, Piccolo, RIM1, and Munc13-1; it directly binds voltage-dependent Ca2+ channel β-subunits to anchor VDCCs at the active zone and modulate their gating, interacts with the tandem PDZ protein syntenin-1 to organize the active-zone cytoskeleton, and undergoes SRPK2-mediated phosphorylation that controls its self-assembly via coiled-coil domains CC1 and CC4."},"narrative":{"mechanistic_narrative":"ERC2/CAST1 is a presynaptic active-zone scaffolding protein that organizes the molecular cytomatrix controlling neurotransmitter release and couples it to calcium influx [PMID:22577167, PMID:16421316]. It directly binds the β4- (and more weakly β1b-) subunits of voltage-dependent Ca2+ channels, and this interaction shifts the voltage dependence of channel activation toward hyperpolarization, functionally tuning Ca2+ channel gating at the active zone [PMID:22577167]. Reciprocally, P/Q- and N-type VDCCs act as membrane anchors that recruit ERC2 together with Bassoon and Piccolo to the active zone; loss of these channels reduces active-zone number, docked vesicle pools, and active-zone protein levels including ERC2, establishing a mutual scaffolding relationship between the channels and the cytomatrix [PMID:21228161]. ERC2 further organizes the active zone by binding the tandem-PDZ protein syntenin-1 through its C-terminal region, with multimerization of both partners driving syntenin-1 localization to presynaptic ERC2 clusters [PMID:16421316]. Its self-assembly is regulated by SRPK2-mediated phosphorylation acting through the coiled-coil domains CC1 and CC4, controlling the degree of ERC2 oligomerization during active-zone assembly [PMID:31671734]. A somatic ERC2 L309I mutation has been linked to Maffucci's syndrome, where it enhances angiogenesis in vitro [PMID:34790172].","teleology":[{"year":2006,"claim":"Established that ERC2 acts as a PDZ-organizing scaffold by identifying syntenin-1 as a direct C-terminal binding partner recruited to presynaptic ERC2 clusters, defining one route by which ERC2 builds active-zone molecular architecture.","evidence":"Yeast two-hybrid, reciprocal co-IP with domain mapping, and immunofluorescence colocalization in neurons","pmids":["16421316"],"confidence":"Medium","gaps":["Functional consequence of syntenin-1 recruitment for release was not measured","Single-lab finding without independent replication","Role of multimerization in vivo not tested"]},{"year":2011,"claim":"Showed that VDCCs themselves anchor ERC2 to the active zone, reframing the channel as a scaffolding hub whose loss disassembles active-zone structure and depletes ERC2.","evidence":"P/Q- and N-type VDCC double-knockout mouse with quantitative electron microscopy and confirmatory co-IP of β-subunit–ERC2 binding","pmids":["21228161"],"confidence":"High","gaps":["Did not resolve whether ERC2 loss is direct or secondary to active-zone collapse","Stoichiometry of the channel–scaffold complex not defined"]},{"year":2012,"claim":"Demonstrated that the ERC2–VDCC interaction is not merely structural but functional, showing ERC2 binding to the β4-subunit modulates Ca2+ channel gating.","evidence":"Co-IP from mouse brain, pull-down domain mapping, and heterologous coexpression with electrophysiology in BHK cells","pmids":["22577167"],"confidence":"High","gaps":["Physiological impact of the gating shift on release probability not measured in neurons","Weak β-subunit/α1-linker interactions not fully resolved"]},{"year":2019,"claim":"Identified a regulatory mechanism for ERC2 assembly, showing SRPK2 phosphorylates ERC2 to control its coiled-coil-dependent self-oligomerization during active-zone formation.","evidence":"Co-IP in HEK293T, SH-SY5Y and HT-22 cells, overexpression/dominant-negative manipulation, and synaptosomal fractionation","pmids":["31671734"],"confidence":"Medium","gaps":["Phosphosite identity and stoichiometry not mapped","Effect on active-zone assembly shown in cell lines, not neurons in vivo","Single-lab finding"]},{"year":2021,"claim":"Linked ERC2 to a disease context outside the synapse, finding a somatic L309I mutation associated with Maffucci's syndrome that enhances angiogenesis.","evidence":"Exome sequencing of a single patient, PCR confirmation, and an in vitro angiogenesis assay with the mutant construct","pmids":["34790172"],"confidence":"Low","gaps":["Single case with limited mechanistic detail; not independently confirmed","Connection between active-zone scaffolding function and angiogenesis unexplained","No in vivo model of the mutation"]},{"year":null,"claim":"How ERC2's calcium-channel anchoring, syntenin-1/PDZ organization, and SRPK2-regulated oligomerization are coordinated dynamically to set release probability remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of the ERC2–VDCC–Bassoon/Piccolo cytomatrix","Temporal order of phosphorylation, oligomerization, and channel recruitment unknown","Direct effect of ERC2 manipulation on neurotransmitter release kinetics not established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1]}],"complexes":["presynaptic active-zone cytomatrix"],"partners":["CACNB4","CACNB1","SDCBP","SRPK2","BSN","PCLO"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15083","full_name":"ERC protein 2","aliases":[],"length_aa":957,"mass_kda":110.6,"function":"Thought to be involved in the organization of the cytomatrix at the nerve terminals active zone (CAZ) which regulates neurotransmitter release. Seems to act together with BSN. May recruit liprin-alpha proteins to the CAZ","subcellular_location":"Cytoplasm; Synapse; Presynaptic active zone; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/O15083/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ERC2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ERC2","total_profiled":1310},"omim":[{"mim_id":"617250","title":"ELKS/RAB6-INTERACTING/CAST FAMILY, MEMBER 2; ERC2","url":"https://www.omim.org/entry/617250"},{"mim_id":"609894","title":"UNC13 HOMOLOG A; UNC13A","url":"https://www.omim.org/entry/609894"},{"mim_id":"606629","title":"PROTEIN REGULATING SYNAPTIC MEMBRANE EXOCYTOSIS 1; RIMS1","url":"https://www.omim.org/entry/606629"},{"mim_id":"604918","title":"PICCOLO PRESYNAPTIC CYTOMATRIX PROTEIN; PCLO","url":"https://www.omim.org/entry/604918"},{"mim_id":"604020","title":"BASSOON PRESYNAPTIC CYTOMATRIX PROTEIN; BSN","url":"https://www.omim.org/entry/604020"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":9.6}],"url":"https://www.proteinatlas.org/search/ERC2"},"hgnc":{"alias_symbol":["CAST","CAST1","KIAA0378","SPBC110","Spc110","ELKSL"],"prev_symbol":[]},"alphafold":{"accession":"O15083","domains":[{"cath_id":"-","chopping":"736-916","consensus_level":"medium","plddt":82.1182,"start":736,"end":916}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15083","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15083-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15083-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ERC2","jax_strain_url":"https://www.jax.org/strain/search?query=ERC2"},"sequence":{"accession":"O15083","fasta_url":"https://rest.uniprot.org/uniprotkb/O15083.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15083/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15083"}},"corpus_meta":[{"pmid":"21228161","id":"PMC_21228161","title":"Calcium channels link the muscle-derived synapse organizer laminin β2 to Bassoon and CAST/Erc2 to organize presynaptic active zones.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21228161","citation_count":86,"is_preprint":false},{"pmid":"22577167","id":"PMC_22577167","title":"Physical and functional interaction of the active zone protein CAST/ERC2 and the β-subunit of the voltage-dependent Ca(2+) channel.","date":"2012","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22577167","citation_count":55,"is_preprint":false},{"pmid":"16421316","id":"PMC_16421316","title":"Organization of the presynaptic active zone by ERC2/CAST1-dependent clustering of the tandem PDZ protein syntenin-1.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16421316","citation_count":37,"is_preprint":false},{"pmid":"9920414","id":"PMC_9920414","title":"The fork head transcription factor Hcm1p participates in the regulation of SPC110, which encodes the calmodulin-binding protein in the yeast spindle pole body.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9920414","citation_count":25,"is_preprint":false},{"pmid":"11118641","id":"PMC_11118641","title":"Mutations in SPC110, encoding the yeast spindle pole body calmodulin-binding protein, cause defects in cell integrity as well as spindle formation.","date":"2000","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11118641","citation_count":22,"is_preprint":false},{"pmid":"31671734","id":"PMC_31671734","title":"Serine-Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31671734","citation_count":10,"is_preprint":false},{"pmid":"34790172","id":"PMC_34790172","title":"IDH1 R132C and ERC2 L309I Mutations Contribute to the Development of Maffucci's Syndrome.","date":"2021","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34790172","citation_count":7,"is_preprint":false},{"pmid":"32374651","id":"PMC_32374651","title":"Yeast pericentrin/Spc110 contains multiple domains required for tethering the γ-tubulin complex to the centrosome.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32374651","citation_count":4,"is_preprint":false},{"pmid":"36259662","id":"PMC_36259662","title":"Phosphosites of the yeast centrosome component Spc110 contribute to cell cycle progression and mitotic exit.","date":"2022","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/36259662","citation_count":3,"is_preprint":false},{"pmid":"39212851","id":"PMC_39212851","title":"Exploitation and Application of a New Genetic Sex Marker Based on Intron Insertion Variation of erc2 Gene in Oplegnathus punctatus.","date":"2024","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39212851","citation_count":3,"is_preprint":false},{"pmid":"36555116","id":"PMC_36555116","title":"Circ-ERC2 Is Involved in Melatonin Synthesis by Regulating the miR-125a-5p/MAT2A Axis.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36555116","citation_count":3,"is_preprint":false},{"pmid":"40774815","id":"PMC_40774815","title":"ERC2.0 evolutionary rate covariation update improves inference of functional interactions across large phylogenies.","date":"2025","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/40774815","citation_count":1,"is_preprint":false},{"pmid":"30544205","id":"PMC_30544205","title":"Potential clinical utility of ERC-2 yeast phase lysate antigen for antibody detection in dogs with blastomycosis.","date":"2019","source":"Medical mycology","url":"https://pubmed.ncbi.nlm.nih.gov/30544205","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.03.25336901","title":"Genetic correlation analysis identifies <i>TMEM106B, ACE</i>, and <i>ERC2</i> as genetic loci shared between Alzheimer’s disease and primary psychiatric disorders","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.03.25336901","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9643,"output_tokens":1412,"usd":0.025055,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8098,"output_tokens":2399,"usd":0.050232,"stage2_stop_reason":"end_turn"},"total_usd":0.075287,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"CAST/ERC2 directly interacts with the VDCC β4-subunit (and more weakly with the α1-subunit II-III linker) at presynaptic active zones; co-immunoprecipitation from mouse brain and pull-down assays confirmed this interaction. Coexpression of CAST and VDCCs in BHK cells shifted voltage dependence of VDCC activation toward the hyperpolarizing direction, indicating that the interaction functionally modulates Ca2+ channel gating.\",\n      \"method\": \"Co-immunoprecipitation from mouse brain, pull-down assay, heterologous coexpression with electrophysiology\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal co-IP from native tissue, direct pull-down mapping domains, and functional electrophysiology readout in single focused study\",\n      \"pmids\": [\"22577167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"P/Q- and N-type VDCCs act as scaffolding proteins that anchor CAST/ERC2 (together with Bassoon and Piccolo) to the presynaptic active zone membrane. Double knockout of P/Q- and N-type VDCCs in mice reduced the number of active zones, docked vesicles, and active-zone protein levels including CAST/ERC2. Direct interaction between VDCC β-subunits (β1b or β4) and CAST/ERC2 was confirmed by immunoprecipitation.\",\n      \"method\": \"Double knockout mouse model, immunoprecipitation, quantitative electron microscopy of active zones\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with defined ultrastructural phenotype plus confirmatory co-IP; replicated the CAST–β-subunit interaction found independently by Kiyonaka et al.\",\n      \"pmids\": [\"21228161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ERC2/CAST1 interacts with the tandem PDZ protein syntenin-1 via a PDZ interaction involving the C-terminal region of ERC2. This interaction, together with multimerization of both ERC2 and syntenin-1, promotes the localization of syntenin-1 at presynaptic ERC2 clusters, thereby contributing to molecular organization of the presynaptic active zone.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence colocalization in neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal binding assays with domain mapping plus colocalization, single lab\",\n      \"pmids\": [\"16421316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRPK2 physically interacts with CAST1/ERC2 and phosphorylates it to regulate its self-assembly. Overexpression of SRPK2 in HEK293T, SH-SY5Y, and HT-22 cells modulated CAST1/ERC2 self-assembly (coiled-coil CC1 and CC4 domains involved). SRPK2 was detected in brain synaptic fractions, consistent with a synaptic role in controlling the level of CAST1/ERC2 oligomerization during presynaptic active-zone assembly.\",\n      \"method\": \"Co-immunoprecipitation in HEK293T and SH-SY5Y cells, overexpression/dominant-negative approach, synaptosomal fractionation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP in multiple cell lines with domain mapping, synaptic fractionation, single lab\",\n      \"pmids\": [\"31671734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A somatic missense mutation ERC2 L309I was identified in a patient with Maffucci's syndrome; in vitro experiments showed this mutation enhances angiogenesis, implicating ERC2 in a role that promotes hypervascularization when mutated.\",\n      \"method\": \"Exome sequencing, PCR confirmation, in vitro angiogenesis assay with mutant construct\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single case, in vitro assay with limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"34790172\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ERC2/CAST1 is a presynaptic active-zone scaffolding protein that forms a cytomatrix complex with Bassoon, Piccolo, RIM1, and Munc13-1; it directly binds voltage-dependent Ca2+ channel β-subunits to anchor VDCCs at the active zone and modulate their gating, interacts with the tandem PDZ protein syntenin-1 to organize the active-zone cytoskeleton, and undergoes SRPK2-mediated phosphorylation that controls its self-assembly via coiled-coil domains CC1 and CC4.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ERC2/CAST1 is a presynaptic active-zone scaffolding protein that organizes the molecular cytomatrix controlling neurotransmitter release and couples it to calcium influx [#0, #2]. It directly binds the β4- (and more weakly β1b-) subunits of voltage-dependent Ca2+ channels, and this interaction shifts the voltage dependence of channel activation toward hyperpolarization, functionally tuning Ca2+ channel gating at the active zone [#0]. Reciprocally, P/Q- and N-type VDCCs act as membrane anchors that recruit ERC2 together with Bassoon and Piccolo to the active zone; loss of these channels reduces active-zone number, docked vesicle pools, and active-zone protein levels including ERC2, establishing a mutual scaffolding relationship between the channels and the cytomatrix [#1]. ERC2 further organizes the active zone by binding the tandem-PDZ protein syntenin-1 through its C-terminal region, with multimerization of both partners driving syntenin-1 localization to presynaptic ERC2 clusters [#2]. Its self-assembly is regulated by SRPK2-mediated phosphorylation acting through the coiled-coil domains CC1 and CC4, controlling the degree of ERC2 oligomerization during active-zone assembly [#3]. A somatic ERC2 L309I mutation has been linked to Maffucci's syndrome, where it enhances angiogenesis in vitro [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that ERC2 acts as a PDZ-organizing scaffold by identifying syntenin-1 as a direct C-terminal binding partner recruited to presynaptic ERC2 clusters, defining one route by which ERC2 builds active-zone molecular architecture.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP with domain mapping, and immunofluorescence colocalization in neurons\",\n      \"pmids\": [\"16421316\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional consequence of syntenin-1 recruitment for release was not measured\",\n        \"Single-lab finding without independent replication\",\n        \"Role of multimerization in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that VDCCs themselves anchor ERC2 to the active zone, reframing the channel as a scaffolding hub whose loss disassembles active-zone structure and depletes ERC2.\",\n      \"evidence\": \"P/Q- and N-type VDCC double-knockout mouse with quantitative electron microscopy and confirmatory co-IP of β-subunit–ERC2 binding\",\n      \"pmids\": [\"21228161\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Did not resolve whether ERC2 loss is direct or secondary to active-zone collapse\",\n        \"Stoichiometry of the channel–scaffold complex not defined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that the ERC2–VDCC interaction is not merely structural but functional, showing ERC2 binding to the β4-subunit modulates Ca2+ channel gating.\",\n      \"evidence\": \"Co-IP from mouse brain, pull-down domain mapping, and heterologous coexpression with electrophysiology in BHK cells\",\n      \"pmids\": [\"22577167\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Physiological impact of the gating shift on release probability not measured in neurons\",\n        \"Weak β-subunit/α1-linker interactions not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a regulatory mechanism for ERC2 assembly, showing SRPK2 phosphorylates ERC2 to control its coiled-coil-dependent self-oligomerization during active-zone formation.\",\n      \"evidence\": \"Co-IP in HEK293T, SH-SY5Y and HT-22 cells, overexpression/dominant-negative manipulation, and synaptosomal fractionation\",\n      \"pmids\": [\"31671734\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Phosphosite identity and stoichiometry not mapped\",\n        \"Effect on active-zone assembly shown in cell lines, not neurons in vivo\",\n        \"Single-lab finding\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ERC2 to a disease context outside the synapse, finding a somatic L309I mutation associated with Maffucci's syndrome that enhances angiogenesis.\",\n      \"evidence\": \"Exome sequencing of a single patient, PCR confirmation, and an in vitro angiogenesis assay with the mutant construct\",\n      \"pmids\": [\"34790172\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Single case with limited mechanistic detail; not independently confirmed\",\n        \"Connection between active-zone scaffolding function and angiogenesis unexplained\",\n        \"No in vivo model of the mutation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ERC2's calcium-channel anchoring, syntenin-1/PDZ organization, and SRPK2-regulated oligomerization are coordinated dynamically to set release probability remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No integrated structural model of the ERC2–VDCC–Bassoon/Piccolo cytomatrix\",\n        \"Temporal order of phosphorylation, oligomerization, and channel recruitment unknown\",\n        \"Direct effect of ERC2 manipulation on neurotransmitter release kinetics not established in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"presynaptic active-zone cytomatrix\"],\n    \"partners\": [\"CACNB4\", \"CACNB1\", \"SDCBP\", \"SRPK2\", \"BSN\", \"PCLO\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}