{"gene":"CAV3","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1992,"finding":"VIP21 (caveolin-3 precursor) is an integral membrane protein component of trans-Golgi-network-derived transport vesicles and localizes to the Golgi apparatus, plasma membrane, and vesicular structures, suggesting a role in vesicular transport machinery.","method":"cDNA cloning, detergent solubilization of Golgi-derived vesicles, CHAPS-insoluble complex isolation, transient expression/immunolocalization","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical fractionation and localization in a single lab with multiple complementary approaches","pmids":["1512286"],"is_preprint":false},{"year":1992,"finding":"Human caveolin (CAV3 locus product) is the same protein as VIP21, an integral membrane protein; Northern blot confirmed that caveolin mRNA is elevated in muscle tissue.","method":"cDNA sequencing, sequence homology analysis, Northern blotting, genomic Southern blotting","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and expression analysis establishing identity, single lab","pmids":["1360410"],"is_preprint":false},{"year":1994,"finding":"VIP21-caveolin is localized to both caveolae (plasma membrane) and the trans-Golgi network, and forms high-molecular-mass oligomers (a key structural feature), implicating it in membrane protein sorting.","method":"Immunolocalization, biochemical fractionation, SDS-PAGE analysis of oligomeric complexes","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization and biochemical characterization, single lab but consistent with other reports","pmids":["8206165"],"is_preprint":false},{"year":1994,"finding":"VIP21/caveolin is required for recruiting GPI-anchored proteins into glycosphingolipid complexes necessary for apical sorting; FRT cells lacking VIP21/caveolin expression fail to cluster GPI-anchored proteins with glycosphingolipids, resulting in basolateral mistargeting.","method":"Comparison of cell lines differing in VIP21/caveolin expression, TX-100 insolubility assays, isopycnic density gradient centrifugation, apical/basolateral sorting assays","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — natural loss-of-function (caveolin-negative FRT cells) with rescue concept, multiple orthogonal methods, replicated across multiple cell lines","pmids":["8306971"],"is_preprint":false},{"year":1995,"finding":"VIP21/caveolin (CAV3) binds cholesterol directly (at least 1 mol cholesterol per mol protein) and this cholesterol binding promotes formation of protein oligomers; the protein reconstitutes into liposomes only with cholesterol-containing lipid mixtures.","method":"In vitro reconstitution of E. coli-expressed VIP21 into liposomes, cholesterol-binding assay, oligomerization assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with purified protein, cholesterol-binding quantitation, oligomer formation demonstrated biochemically","pmids":["7479780"],"is_preprint":false},{"year":1995,"finding":"VIP21-caveolin is a key structural component required for caveolar biogenesis; de novo expression of VIP21-caveolin in lymphocytes (which normally lack caveolae) is sufficient to drive formation of morphologically normal plasma membrane caveolae and recruit GPI-anchored proteins (Thy1) to these structures.","method":"Semliki Forest virus expression system in lymphocytes, electron microscopy, immunofluorescence, antibody patching of GPI-anchored proteins","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — gain-of-function reconstitution in a cell type naturally lacking caveolae, with direct structural (EM) and functional (GPI-protein recruitment) readouts","pmids":["7567992"],"is_preprint":false},{"year":1995,"finding":"VIP21-caveolin forms homo-oligomers of ~200, 400, and 600 kDa; oligomers form early in the ER via classical translocation machinery, with the hydrophobic domain adopting a hairpin loop configuration exposing both N- and C-flanking regions to the cytoplasm; oligomer formation is cytosol-dependent but does not require vesicle fusion.","method":"SDS-PAGE analysis of detergent-insoluble complexes, pulse-chase experiments, in vitro translation/membrane insertion, sucrose gradient ultracentrifugation, purification of 400-kDa complex from dog lung","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods including in vitro reconstitution, pulse-chase, and native complex purification in a single rigorous study","pmids":["7579702"],"is_preprint":false},{"year":1995,"finding":"A photo-reactive ganglioside GM1 derivative specifically cross-links VIP21-caveolin at the cell surface, demonstrating direct proximity between GM1 and caveolin in the caveolar membrane and implicating sphingolipid segregation in caveolar biogenesis.","method":"Photoaffinity cross-linking with radiolabeled GM1 derivative, SDS-PAGE, autoradiography in A431 and MDCK cells","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chemical cross-linking demonstrating proximity, replicated in two cell lines, single lab","pmids":["7498456"],"is_preprint":false},{"year":1996,"finding":"Long-chain fatty acyl-CoA esters can substitute for cytosol in inducing VIP21-caveolin oligomerization (200 and 400 kDa forms); 25-hydroxycholesterol produces the 200 kDa oligomer. Palmitoylation of cysteine residues is not required for oligomerization per se but increases stability of oligomers (non-palmitoylated oligomers are disrupted by SDS-PAGE without boiling whereas palmitoylated ones are not), establishing that protein domains are the primary determinants of oligomerization.","method":"In vitro synthesis and membrane insertion of VIP21-caveolin, cytosol substitution with lipids/fatty acyl-CoA, cysteine-to-alanine mutagenesis, sucrose velocity gradient centrifugation in octylglucoside, SDS-PAGE with/without boiling","journal":"FEBS Letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple lipid conditions, mechanistically resolved the roles of acylation vs. protein domains","pmids":["8690074"],"is_preprint":false},{"year":1999,"finding":"Caveolin-1 (VIP-21) cycles between the plasma membrane caveolae and intracellular endocytic compartments including early-sorting endosomes (CURL) and the receptor-recycling compartment in hepatocytes; retinol-binding protein administration caused redistribution of caveolin-1 from plasma membrane to these endocytic compartments, demonstrating dynamic trafficking of caveolae.","method":"Subcellular fractionation of rat liver, electron microscopy, immunoblotting of fractions, intravenous administration of retinol-binding protein and tracking of caveolin-1 redistribution","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct fractionation with functional stimulus (RBP administration) showing redistribution, single lab","pmids":["10347129"],"is_preprint":false},{"year":2000,"finding":"A novel sporadic CAV3 gene mutation causes partial caveolin-3 deficiency (reduced protein expression in muscle fibers) leading to hyperCKemia without muscle weakness, establishing that partial caveolin-3 deficiency is sufficient to disrupt muscle membrane integrity.","method":"CAV3 gene sequencing, immunohistochemistry of muscle biopsies, quantitative immunoblot analysis","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function (mutation) with direct protein quantification, replicated in two unrelated patients","pmids":["10746614"],"is_preprint":false},{"year":2003,"finding":"A CAV3 3-bp microdeletion (Phe97del) in the transmembrane domain causes severe caveolin-3 deficiency and caveolar disorganization in skeletal muscle, but only ~40% reduction in myocardium where caveolin-3 is correctly localized with preserved caveolar structures, demonstrating that the molecular network interacting with caveolin-3 differs between skeletal and cardiac muscle.","method":"CAV3 genetic analysis, immunohistochemistry, western blot, electron microscopy of muscle and heart biopsies","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct tissue comparison of protein levels and ultrastructure, multiple methods, single family","pmids":["14663034"],"is_preprint":false},{"year":2010,"finding":"Caveolin-3 (Cav-3) co-localizes with and regulates Cav3.2 T-type calcium channels in cardiomyocytes: immunogold EM demonstrated co-localization at caveolae; co-immunoprecipitation confirmed physical association of Cav3.2 and Cav3.1 with Cav-3; GST pulldown showed the N-terminus of Cav-3 interacts with Cav3.2; Cav-3 co-expression decreased peak Cav3.2 current density; PKA-dependent stimulation of T-type current was abolished by Cav-3 siRNA knockdown.","method":"Immunogold electron microscopy, co-immunoprecipitation from neonatal ventricular myocytes and HEK293 cells, GST pulldown, whole-cell patch clamp, siRNA knockdown, adenoviral overexpression","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (EM co-localization, co-IP, GST pulldown, electrophysiology, RNAi) in both native cardiomyocytes and heterologous system, single rigorous study","pmids":["21084288"],"is_preprint":false},{"year":2013,"finding":"Caveolin-3 (Cav3) associates physically with the inward rectifier potassium channel Kir2.1; LQT9-associated CAV3 mutations (F97C, T78M, P104L) decrease Kir2.1 current density by ~30–60% by reducing Kir2.1 cell surface expression, not by altering intrinsic channel gating. Co-immunoprecipitation, FRET analysis (molecular distance 5.6 ± 0.4 nm), and colocalization in Golgi confirmed the physical interaction.","method":"Whole-cell voltage clamp, co-immunoprecipitation from human ventricular myocytes and HEK293 cells, confocal imaging, FRET analysis, on-cell Western blot for surface expression","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, co-IP, FRET, surface expression assay) in both native human tissue and heterologous system, mechanistically defined pathway","pmids":["23640888"],"is_preprint":false},{"year":2023,"finding":"ANKRD1 modulates CAV3 expression by reducing caveolin-3 ubiquitination, thereby increasing caveolin-3 protein stability; ANKRD1-mediated promotion of Wnt/β-catenin signaling in BMSCs is dependent on CAV3, as CAV3 knockdown impairs ANKRD1's osteogenic effects.","method":"Lentiviral ANKRD1 silencing/overexpression, ubiquitination assays, Wnt/β-catenin reporter assays, siRNA knockdown of CAV3, osteogenic differentiation assays, micro-CT in ovariectomized mice","journal":"Biochimica et Biophysica Acta. Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue/knockdown experiments with ubiquitination mechanism, single lab","pmids":["36958710"],"is_preprint":false}],"current_model":"CAV3 (caveolin-3) is a muscle-enriched integral membrane protein that directly binds cholesterol and oligomerizes into high-molecular-mass complexes (200–600 kDa) through its protein domains, with palmitoylation stabilizing but not required for oligomers; these oligomers form in the ER and are required for de novo biogenesis of caveolae at the plasma membrane, where caveolin-3 organizes lipid microdomains enriched in sphingolipids/cholesterol to recruit GPI-anchored proteins; it also scaffolds signaling complexes at caveolae, including physical interaction with Kir2.1 (loss-of-function CAV3 mutations causing LQT9 reduce Kir2.1 surface expression) and with Cav3.2 T-type calcium channels (suppressing their current density and gating the PKA-dependent regulation of T-type current in cardiomyocytes); CAV3 mutations disrupt caveolar structure and caveolin-3 protein levels in skeletal muscle causing LGMD1C, rippling muscle disease, and hyperCKemia, while effects in cardiac tissue are more variable."},"narrative":{"mechanistic_narrative":"Caveolin-3 (CAV3, originally VIP21-caveolin) is a muscle-enriched integral membrane protein that serves as the principal structural component driving the de novo biogenesis of plasma membrane caveolae [PMID:1360410, PMID:7567992]. It binds cholesterol directly and reconstitutes into membranes only in cholesterol-containing lipid mixtures, and cholesterol binding promotes its assembly into high-molecular-mass homo-oligomers of ~200, 400, and 600 kDa [PMID:7479780, PMID:7579702]. These oligomers form early in the ER, where the hydrophobic domain adopts a hairpin loop exposing both N- and C-terminal regions to the cytoplasm; protein domains are the primary determinants of oligomerization, while palmitoylation of cysteine residues stabilizes but is not required for oligomer formation [PMID:7579702, PMID:8690074]. De novo expression of caveolin-3 in cells lacking caveolae is sufficient to generate morphologically normal caveolae and to recruit GPI-anchored proteins into glycosphingolipid microdomains, organizing apical membrane sorting [PMID:8306971, PMID:7567992]; caveolin is found in direct proximity to ganglioside GM1 at the caveolar membrane [PMID:7498456]. At caveolae, caveolin-3 scaffolds ion channel signaling complexes: it physically associates with Cav3.2 T-type calcium channels via its N-terminus, suppressing their current density and gating PKA-dependent regulation of T-type current in cardiomyocytes [PMID:21084288], and it binds the inward rectifier channel Kir2.1, where long-QT-associated mutations (F97C, T78M, P104L) reduce Kir2.1 surface expression and current density without altering channel gating [PMID:23640888]. CAV3 mutations cause partial-to-severe caveolin-3 deficiency with caveolar disorganization in skeletal muscle, producing hyperCKemia, with effects in myocardium being milder owing to a distinct tissue-specific interaction network [PMID:10746614, PMID:14663034].","teleology":[{"year":1992,"claim":"Establishing the molecular identity of the protein: cloning revealed VIP21/caveolin as an integral membrane protein of trans-Golgi-derived vesicles enriched in muscle, framing it as part of the vesicular transport machinery.","evidence":"cDNA cloning, detergent fractionation of Golgi vesicles, immunolocalization, and Northern blotting","pmids":["1512286","1360410"],"confidence":"Medium","gaps":["Function beyond localization not yet defined","No structural or oligomeric mechanism established"]},{"year":1994,"claim":"Linking caveolin to membrane organization: it localizes to caveolae and the trans-Golgi network, forms high-molecular-mass oligomers, and is required to cluster GPI-anchored proteins with glycosphingolipids for apical sorting.","evidence":"Immunolocalization, biochemical fractionation, and loss-of-function comparison in caveolin-negative FRT cells with sorting assays","pmids":["8206165","8306971"],"confidence":"High","gaps":["Lipid-binding basis of oligomerization not yet shown","Sufficiency for caveola formation not demonstrated"]},{"year":1995,"claim":"Defining the biochemical mechanism of assembly: caveolin binds cholesterol directly, cholesterol drives oligomerization, oligomers form in the ER via a hairpin topology, and de novo expression is sufficient to create caveolae and recruit GPI-anchored proteins.","evidence":"In vitro reconstitution of purified protein into liposomes, cholesterol-binding quantitation, pulse-chase, native complex purification, and gain-of-function expression in lymphocytes with EM","pmids":["7479780","7567992","7579702","7498456"],"confidence":"High","gaps":["Role of acylation versus protein domains unresolved","In vivo muscle function not addressed"]},{"year":1996,"claim":"Resolving the determinants of oligomerization: fatty acyl-CoA and oxysterols can substitute for cytosol to induce oligomers, and palmitoylation stabilizes but is not required, establishing protein domains as the primary drivers.","evidence":"In vitro synthesis/membrane insertion with lipid substitution, cysteine-to-alanine mutagenesis, and SDS-PAGE with/without boiling","pmids":["8690074"],"confidence":"High","gaps":["Physiological lipid trigger in vivo unknown","Link to disease mutations not made"]},{"year":1999,"claim":"Showing caveolae are dynamic: caveolin cycles between plasma membrane caveolae and endocytic compartments, and ligand stimulus redistributes it intracellularly.","evidence":"Subcellular fractionation of rat liver, EM, and tracking of caveolin redistribution after retinol-binding protein administration","pmids":["10347129"],"confidence":"Medium","gaps":["Performed largely on caveolin-1/hepatocyte context","Trafficking machinery not identified"]},{"year":2003,"claim":"Connecting CAV3 mutations to disease and tissue specificity: deficiency-causing mutations disorganize caveolae and cause hyperCKemia in skeletal muscle but spare myocardium, revealing distinct tissue interaction networks.","evidence":"CAV3 sequencing, immunohistochemistry, western blot, and EM of patient muscle and heart biopsies","pmids":["10746614","14663034"],"confidence":"Medium","gaps":["Molecular basis of cardiac sparing not defined","Limited to small patient cohorts"]},{"year":2013,"claim":"Defining caveolin-3 as an ion-channel scaffold: it physically associates with Cav3.2 T-type calcium channels and Kir2.1, regulating their current density and surface expression, and LQT9 mutations act by reducing Kir2.1 trafficking rather than gating.","evidence":"Immunogold EM, co-IP, GST pulldown, FRET, surface-expression assays, and patch clamp in native myocytes and HEK293 cells","pmids":["21084288","23640888"],"confidence":"High","gaps":["Structural basis of channel binding not resolved","In vivo arrhythmia mechanism not directly tested"]},{"year":2023,"claim":"Identifying an upstream regulator of caveolin-3 stability: ANKRD1 reduces caveolin-3 ubiquitination to increase its protein level, and its osteogenic Wnt/β-catenin effects depend on CAV3.","evidence":"Lentiviral ANKRD1 manipulation, ubiquitination assays, Wnt reporter assays, CAV3 knockdown, and micro-CT in ovariectomized mice","pmids":["36958710"],"confidence":"Medium","gaps":["Direct ANKRD1-CAV3 interaction not demonstrated","Relevance to muscle pathology unknown","Single lab"]},{"year":null,"claim":"How caveolin-3 oligomer architecture and its cholesterol/sphingolipid interactions are integrated to scaffold and traffic specific ion channels in muscle, and why cardiac and skeletal tissues respond differently to the same mutation, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the caveolin-3 oligomer-channel complex","Tissue-specific interaction networks uncharacterized","Mechanistic basis of variable cardiac phenotype unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,13]}],"complexes":["caveolin-3 homo-oligomer (caveolar coat)"],"partners":["CACNA1H","KCNJ2","ANKRD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56539","full_name":"Caveolin-3","aliases":["M-caveolin"],"length_aa":151,"mass_kda":17.3,"function":"May act as a scaffolding protein within caveolar membranes. Interacts directly with G-protein alpha subunits and can functionally regulate their activity. May also regulate voltage-gated potassium channels. Plays a role in the sarcolemma repair mechanism of both skeletal muscle and cardiomyocytes that permits rapid resealing of membranes disrupted by mechanical stress (By similarity). Mediates the recruitment of CAVIN2 and CAVIN3 proteins to the caveolae (PubMed:19262564)","subcellular_location":"Golgi apparatus membrane; Cell membrane; Membrane, caveola; Cell membrane, sarcolemma","url":"https://www.uniprot.org/uniprotkb/P56539/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAV3","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/CAV3","total_profiled":1310},"omim":[{"mim_id":"621343","title":"CONGENITAL MYOPATHY 27; CMYO27","url":"https://www.omim.org/entry/621343"},{"mim_id":"620144","title":"CACHE DOMAIN-CONTAINING PROTEIN 1; CACHD1","url":"https://www.omim.org/entry/620144"},{"mim_id":"619863","title":"JUNCTOPHILIN 4; JPH4","url":"https://www.omim.org/entry/619863"},{"mim_id":"619040","title":"MYOFIBRILLAR MYOPATHY 10; MFM10","url":"https://www.omim.org/entry/619040"},{"mim_id":"616795","title":"SPINOCEREBELLAR ATAXIA 42; SCA42","url":"https://www.omim.org/entry/616795"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":171.2},{"tissue":"tongue","ntpm":68.1}],"url":"https://www.proteinatlas.org/search/CAV3"},"hgnc":{"alias_symbol":["VIP-21","LGMD1C","VIP21","LQT9"],"prev_symbol":[]},"alphafold":{"accession":"P56539","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56539","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56539-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56539-F1-predicted_aligned_error_v6.png","plddt_mean":88.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAV3","jax_strain_url":"https://www.jax.org/strain/search?query=CAV3"},"sequence":{"accession":"P56539","fasta_url":"https://rest.uniprot.org/uniprotkb/P56539.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56539/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56539"}},"corpus_meta":[{"pmid":"7479780","id":"PMC_7479780","title":"VIP21/caveolin is a cholesterol-binding protein.","date":"1995","source":"Proceedings of the 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Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25377087","citation_count":18,"is_preprint":false},{"pmid":"19805509","id":"PMC_19805509","title":"Protein kinase C-mediated inhibition of recombinant T-type Cav3.2 channels by neurokinin 1 receptors.","date":"2009","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19805509","citation_count":17,"is_preprint":false},{"pmid":"19903827","id":"PMC_19903827","title":"G protein-mediated inhibition of Cav3.2 T-type channels revisited.","date":"2009","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/19903827","citation_count":17,"is_preprint":false},{"pmid":"26241400","id":"PMC_26241400","title":"CaV3.1 T-Type Ca2+ Channels Contribute to Myogenic Signaling in Rat Retinal Arterioles.","date":"2015","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/26241400","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54166,"output_tokens":4414,"usd":0.114354,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11765,"output_tokens":3348,"usd":0.071263,"stage2_stop_reason":"end_turn"},"total_usd":0.185617,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about CAV3 (caveolin-3, the muscle-specific caveolin) versus other genes that share aliases. The HGNC aliases provided are VIP-21, LGMD1C, VIP21, LQT9 — these all refer to caveolin-3.\n\nHowever, many papers in this corpus are about CaV3.1, CaV3.2, CaV3.3 (T-type calcium channels encoded by CACNA1G, CACNA1H, CACNA1I respectively). These are NOT CAV3/caveolin-3. The \"CaV3\" nomenclature for T-type calcium channels is a pharmacological/electrophysiological naming convention, not the gene symbol CAV3.\n\nI need to carefully separate:\n- Papers about CAV3 = caveolin-3 (muscle-specific, structural protein of caveolae) → INCLUDE\n- Papers about CaV3.x T-type calcium channels (CACNA1G/H/I) → EXCLUDE (symbol collision)\n\nPapers about caveolin-3/CAV3: PMIDs 7479780, 7567992, 1512286, 7579702, 8206165, 7498456, 8306971, 8690074, 1360410, 10347129, 10746614, 14663034, 23640888, 93 (ANKRD1/CAV3), and disease phenotype papers 53, 62, 66, 90, 95.\n\nPaper 47 (PMID 21084288) is specifically about caveolin-3 (Cav-3) regulating T-type Ca2+ channels — this is about CAV3 protein.\nPaper 38 (PMID 23640888) is about caveolin-3 interacting with Kir2.1.\nPaper 93 (PMID 36958710) is about ANKRD1 modulating CAV3 expression.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"VIP21 (caveolin-3 precursor) is an integral membrane protein component of trans-Golgi-network-derived transport vesicles and localizes to the Golgi apparatus, plasma membrane, and vesicular structures, suggesting a role in vesicular transport machinery.\",\n      \"method\": \"cDNA cloning, detergent solubilization of Golgi-derived vesicles, CHAPS-insoluble complex isolation, transient expression/immunolocalization\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical fractionation and localization in a single lab with multiple complementary approaches\",\n      \"pmids\": [\"1512286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Human caveolin (CAV3 locus product) is the same protein as VIP21, an integral membrane protein; Northern blot confirmed that caveolin mRNA is elevated in muscle tissue.\",\n      \"method\": \"cDNA sequencing, sequence homology analysis, Northern blotting, genomic Southern blotting\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and expression analysis establishing identity, single lab\",\n      \"pmids\": [\"1360410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"VIP21-caveolin is localized to both caveolae (plasma membrane) and the trans-Golgi network, and forms high-molecular-mass oligomers (a key structural feature), implicating it in membrane protein sorting.\",\n      \"method\": \"Immunolocalization, biochemical fractionation, SDS-PAGE analysis of oligomeric complexes\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization and biochemical characterization, single lab but consistent with other reports\",\n      \"pmids\": [\"8206165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"VIP21/caveolin is required for recruiting GPI-anchored proteins into glycosphingolipid complexes necessary for apical sorting; FRT cells lacking VIP21/caveolin expression fail to cluster GPI-anchored proteins with glycosphingolipids, resulting in basolateral mistargeting.\",\n      \"method\": \"Comparison of cell lines differing in VIP21/caveolin expression, TX-100 insolubility assays, isopycnic density gradient centrifugation, apical/basolateral sorting assays\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — natural loss-of-function (caveolin-negative FRT cells) with rescue concept, multiple orthogonal methods, replicated across multiple cell lines\",\n      \"pmids\": [\"8306971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VIP21/caveolin (CAV3) binds cholesterol directly (at least 1 mol cholesterol per mol protein) and this cholesterol binding promotes formation of protein oligomers; the protein reconstitutes into liposomes only with cholesterol-containing lipid mixtures.\",\n      \"method\": \"In vitro reconstitution of E. coli-expressed VIP21 into liposomes, cholesterol-binding assay, oligomerization assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with purified protein, cholesterol-binding quantitation, oligomer formation demonstrated biochemically\",\n      \"pmids\": [\"7479780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VIP21-caveolin is a key structural component required for caveolar biogenesis; de novo expression of VIP21-caveolin in lymphocytes (which normally lack caveolae) is sufficient to drive formation of morphologically normal plasma membrane caveolae and recruit GPI-anchored proteins (Thy1) to these structures.\",\n      \"method\": \"Semliki Forest virus expression system in lymphocytes, electron microscopy, immunofluorescence, antibody patching of GPI-anchored proteins\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — gain-of-function reconstitution in a cell type naturally lacking caveolae, with direct structural (EM) and functional (GPI-protein recruitment) readouts\",\n      \"pmids\": [\"7567992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VIP21-caveolin forms homo-oligomers of ~200, 400, and 600 kDa; oligomers form early in the ER via classical translocation machinery, with the hydrophobic domain adopting a hairpin loop configuration exposing both N- and C-flanking regions to the cytoplasm; oligomer formation is cytosol-dependent but does not require vesicle fusion.\",\n      \"method\": \"SDS-PAGE analysis of detergent-insoluble complexes, pulse-chase experiments, in vitro translation/membrane insertion, sucrose gradient ultracentrifugation, purification of 400-kDa complex from dog lung\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods including in vitro reconstitution, pulse-chase, and native complex purification in a single rigorous study\",\n      \"pmids\": [\"7579702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"A photo-reactive ganglioside GM1 derivative specifically cross-links VIP21-caveolin at the cell surface, demonstrating direct proximity between GM1 and caveolin in the caveolar membrane and implicating sphingolipid segregation in caveolar biogenesis.\",\n      \"method\": \"Photoaffinity cross-linking with radiolabeled GM1 derivative, SDS-PAGE, autoradiography in A431 and MDCK cells\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chemical cross-linking demonstrating proximity, replicated in two cell lines, single lab\",\n      \"pmids\": [\"7498456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Long-chain fatty acyl-CoA esters can substitute for cytosol in inducing VIP21-caveolin oligomerization (200 and 400 kDa forms); 25-hydroxycholesterol produces the 200 kDa oligomer. Palmitoylation of cysteine residues is not required for oligomerization per se but increases stability of oligomers (non-palmitoylated oligomers are disrupted by SDS-PAGE without boiling whereas palmitoylated ones are not), establishing that protein domains are the primary determinants of oligomerization.\",\n      \"method\": \"In vitro synthesis and membrane insertion of VIP21-caveolin, cytosol substitution with lipids/fatty acyl-CoA, cysteine-to-alanine mutagenesis, sucrose velocity gradient centrifugation in octylglucoside, SDS-PAGE with/without boiling\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and multiple lipid conditions, mechanistically resolved the roles of acylation vs. protein domains\",\n      \"pmids\": [\"8690074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Caveolin-1 (VIP-21) cycles between the plasma membrane caveolae and intracellular endocytic compartments including early-sorting endosomes (CURL) and the receptor-recycling compartment in hepatocytes; retinol-binding protein administration caused redistribution of caveolin-1 from plasma membrane to these endocytic compartments, demonstrating dynamic trafficking of caveolae.\",\n      \"method\": \"Subcellular fractionation of rat liver, electron microscopy, immunoblotting of fractions, intravenous administration of retinol-binding protein and tracking of caveolin-1 redistribution\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation with functional stimulus (RBP administration) showing redistribution, single lab\",\n      \"pmids\": [\"10347129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A novel sporadic CAV3 gene mutation causes partial caveolin-3 deficiency (reduced protein expression in muscle fibers) leading to hyperCKemia without muscle weakness, establishing that partial caveolin-3 deficiency is sufficient to disrupt muscle membrane integrity.\",\n      \"method\": \"CAV3 gene sequencing, immunohistochemistry of muscle biopsies, quantitative immunoblot analysis\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function (mutation) with direct protein quantification, replicated in two unrelated patients\",\n      \"pmids\": [\"10746614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A CAV3 3-bp microdeletion (Phe97del) in the transmembrane domain causes severe caveolin-3 deficiency and caveolar disorganization in skeletal muscle, but only ~40% reduction in myocardium where caveolin-3 is correctly localized with preserved caveolar structures, demonstrating that the molecular network interacting with caveolin-3 differs between skeletal and cardiac muscle.\",\n      \"method\": \"CAV3 genetic analysis, immunohistochemistry, western blot, electron microscopy of muscle and heart biopsies\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct tissue comparison of protein levels and ultrastructure, multiple methods, single family\",\n      \"pmids\": [\"14663034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Caveolin-3 (Cav-3) co-localizes with and regulates Cav3.2 T-type calcium channels in cardiomyocytes: immunogold EM demonstrated co-localization at caveolae; co-immunoprecipitation confirmed physical association of Cav3.2 and Cav3.1 with Cav-3; GST pulldown showed the N-terminus of Cav-3 interacts with Cav3.2; Cav-3 co-expression decreased peak Cav3.2 current density; PKA-dependent stimulation of T-type current was abolished by Cav-3 siRNA knockdown.\",\n      \"method\": \"Immunogold electron microscopy, co-immunoprecipitation from neonatal ventricular myocytes and HEK293 cells, GST pulldown, whole-cell patch clamp, siRNA knockdown, adenoviral overexpression\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (EM co-localization, co-IP, GST pulldown, electrophysiology, RNAi) in both native cardiomyocytes and heterologous system, single rigorous study\",\n      \"pmids\": [\"21084288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Caveolin-3 (Cav3) associates physically with the inward rectifier potassium channel Kir2.1; LQT9-associated CAV3 mutations (F97C, T78M, P104L) decrease Kir2.1 current density by ~30–60% by reducing Kir2.1 cell surface expression, not by altering intrinsic channel gating. Co-immunoprecipitation, FRET analysis (molecular distance 5.6 ± 0.4 nm), and colocalization in Golgi confirmed the physical interaction.\",\n      \"method\": \"Whole-cell voltage clamp, co-immunoprecipitation from human ventricular myocytes and HEK293 cells, confocal imaging, FRET analysis, on-cell Western blot for surface expression\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (electrophysiology, co-IP, FRET, surface expression assay) in both native human tissue and heterologous system, mechanistically defined pathway\",\n      \"pmids\": [\"23640888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANKRD1 modulates CAV3 expression by reducing caveolin-3 ubiquitination, thereby increasing caveolin-3 protein stability; ANKRD1-mediated promotion of Wnt/β-catenin signaling in BMSCs is dependent on CAV3, as CAV3 knockdown impairs ANKRD1's osteogenic effects.\",\n      \"method\": \"Lentiviral ANKRD1 silencing/overexpression, ubiquitination assays, Wnt/β-catenin reporter assays, siRNA knockdown of CAV3, osteogenic differentiation assays, micro-CT in ovariectomized mice\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue/knockdown experiments with ubiquitination mechanism, single lab\",\n      \"pmids\": [\"36958710\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAV3 (caveolin-3) is a muscle-enriched integral membrane protein that directly binds cholesterol and oligomerizes into high-molecular-mass complexes (200–600 kDa) through its protein domains, with palmitoylation stabilizing but not required for oligomers; these oligomers form in the ER and are required for de novo biogenesis of caveolae at the plasma membrane, where caveolin-3 organizes lipid microdomains enriched in sphingolipids/cholesterol to recruit GPI-anchored proteins; it also scaffolds signaling complexes at caveolae, including physical interaction with Kir2.1 (loss-of-function CAV3 mutations causing LQT9 reduce Kir2.1 surface expression) and with Cav3.2 T-type calcium channels (suppressing their current density and gating the PKA-dependent regulation of T-type current in cardiomyocytes); CAV3 mutations disrupt caveolar structure and caveolin-3 protein levels in skeletal muscle causing LGMD1C, rippling muscle disease, and hyperCKemia, while effects in cardiac tissue are more variable.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Caveolin-3 (CAV3, originally VIP21-caveolin) is a muscle-enriched integral membrane protein that serves as the principal structural component driving the de novo biogenesis of plasma membrane caveolae [#1, #5]. It binds cholesterol directly and reconstitutes into membranes only in cholesterol-containing lipid mixtures, and cholesterol binding promotes its assembly into high-molecular-mass homo-oligomers of ~200, 400, and 600 kDa [#4, #6]. These oligomers form early in the ER, where the hydrophobic domain adopts a hairpin loop exposing both N- and C-terminal regions to the cytoplasm; protein domains are the primary determinants of oligomerization, while palmitoylation of cysteine residues stabilizes but is not required for oligomer formation [#6, #8]. De novo expression of caveolin-3 in cells lacking caveolae is sufficient to generate morphologically normal caveolae and to recruit GPI-anchored proteins into glycosphingolipid microdomains, organizing apical membrane sorting [#3, #5]; caveolin is found in direct proximity to ganglioside GM1 at the caveolar membrane [#7]. At caveolae, caveolin-3 scaffolds ion channel signaling complexes: it physically associates with Cav3.2 T-type calcium channels via its N-terminus, suppressing their current density and gating PKA-dependent regulation of T-type current in cardiomyocytes [#12], and it binds the inward rectifier channel Kir2.1, where long-QT-associated mutations (F97C, T78M, P104L) reduce Kir2.1 surface expression and current density without altering channel gating [#13]. CAV3 mutations cause partial-to-severe caveolin-3 deficiency with caveolar disorganization in skeletal muscle, producing hyperCKemia, with effects in myocardium being milder owing to a distinct tissue-specific interaction network [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the molecular identity of the protein: cloning revealed VIP21/caveolin as an integral membrane protein of trans-Golgi-derived vesicles enriched in muscle, framing it as part of the vesicular transport machinery.\",\n      \"evidence\": \"cDNA cloning, detergent fractionation of Golgi vesicles, immunolocalization, and Northern blotting\",\n      \"pmids\": [\"1512286\", \"1360410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function beyond localization not yet defined\", \"No structural or oligomeric mechanism established\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Linking caveolin to membrane organization: it localizes to caveolae and the trans-Golgi network, forms high-molecular-mass oligomers, and is required to cluster GPI-anchored proteins with glycosphingolipids for apical sorting.\",\n      \"evidence\": \"Immunolocalization, biochemical fractionation, and loss-of-function comparison in caveolin-negative FRT cells with sorting assays\",\n      \"pmids\": [\"8206165\", \"8306971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-binding basis of oligomerization not yet shown\", \"Sufficiency for caveola formation not demonstrated\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defining the biochemical mechanism of assembly: caveolin binds cholesterol directly, cholesterol drives oligomerization, oligomers form in the ER via a hairpin topology, and de novo expression is sufficient to create caveolae and recruit GPI-anchored proteins.\",\n      \"evidence\": \"In vitro reconstitution of purified protein into liposomes, cholesterol-binding quantitation, pulse-chase, native complex purification, and gain-of-function expression in lymphocytes with EM\",\n      \"pmids\": [\"7479780\", \"7567992\", \"7579702\", \"7498456\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of acylation versus protein domains unresolved\", \"In vivo muscle function not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Resolving the determinants of oligomerization: fatty acyl-CoA and oxysterols can substitute for cytosol to induce oligomers, and palmitoylation stabilizes but is not required, establishing protein domains as the primary drivers.\",\n      \"evidence\": \"In vitro synthesis/membrane insertion with lipid substitution, cysteine-to-alanine mutagenesis, and SDS-PAGE with/without boiling\",\n      \"pmids\": [\"8690074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological lipid trigger in vivo unknown\", \"Link to disease mutations not made\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showing caveolae are dynamic: caveolin cycles between plasma membrane caveolae and endocytic compartments, and ligand stimulus redistributes it intracellularly.\",\n      \"evidence\": \"Subcellular fractionation of rat liver, EM, and tracking of caveolin redistribution after retinol-binding protein administration\",\n      \"pmids\": [\"10347129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed largely on caveolin-1/hepatocyte context\", \"Trafficking machinery not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connecting CAV3 mutations to disease and tissue specificity: deficiency-causing mutations disorganize caveolae and cause hyperCKemia in skeletal muscle but spare myocardium, revealing distinct tissue interaction networks.\",\n      \"evidence\": \"CAV3 sequencing, immunohistochemistry, western blot, and EM of patient muscle and heart biopsies\",\n      \"pmids\": [\"10746614\", \"14663034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of cardiac sparing not defined\", \"Limited to small patient cohorts\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining caveolin-3 as an ion-channel scaffold: it physically associates with Cav3.2 T-type calcium channels and Kir2.1, regulating their current density and surface expression, and LQT9 mutations act by reducing Kir2.1 trafficking rather than gating.\",\n      \"evidence\": \"Immunogold EM, co-IP, GST pulldown, FRET, surface-expression assays, and patch clamp in native myocytes and HEK293 cells\",\n      \"pmids\": [\"21084288\", \"23640888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of channel binding not resolved\", \"In vivo arrhythmia mechanism not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying an upstream regulator of caveolin-3 stability: ANKRD1 reduces caveolin-3 ubiquitination to increase its protein level, and its osteogenic Wnt/\\u03b2-catenin effects depend on CAV3.\",\n      \"evidence\": \"Lentiviral ANKRD1 manipulation, ubiquitination assays, Wnt reporter assays, CAV3 knockdown, and micro-CT in ovariectomized mice\",\n      \"pmids\": [\"36958710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ANKRD1-CAV3 interaction not demonstrated\", \"Relevance to muscle pathology unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How caveolin-3 oligomer architecture and its cholesterol/sphingolipid interactions are integrated to scaffold and traffic specific ion channels in muscle, and why cardiac and skeletal tissues respond differently to the same mutation, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the caveolin-3 oligomer-channel complex\", \"Tissue-specific interaction networks uncharacterized\", \"Mechanistic basis of variable cardiac phenotype unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 13]}\n    ],\n    \"complexes\": [\"caveolin-3 homo-oligomer (caveolar coat)\"],\n    \"partners\": [\"CACNA1H\", \"KCNJ2\", \"ANKRD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}