{"gene":"C2","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1989,"finding":"Full-length cDNA cloning of human complement C2 revealed a 732-amino acid mature polypeptide with a signal peptide; transfection of the cDNA into COS cells produced a secreted protein with antigenicity and hemolytic activity indistinguishable from native serum C2, confirming the cDNA encodes the functional protein.","method":"cDNA cloning, COS cell expression, Western blot, hemolytic activity assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of functional protein from cloned cDNA with hemolytic activity validation and Western blot in a single rigorous study","pmids":["2493504"],"is_preprint":false},{"year":1984,"finding":"C2 and Factor B are homologous serine proteases encoded by adjacent single-copy loci in the MHC class III region; C2 contains the catalytic site of the classical pathway C3 convertase (C4b2a), and both proteins share structural homology in their catalytic chains while their non-catalytic chains contain three tandem complement-control-protein repeats.","method":"Amino acid sequencing of CNBr peptides, protein homology analysis, biochemical characterization of convertase activity","journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical sequencing and functional characterization replicated across multiple labs","pmids":["6149575","6149579"],"is_preprint":false},{"year":1984,"finding":"The C2 gene spans approximately 18 kb of DNA and lies less than 500 bp from the Factor B gene on chromosome 6; genomic Southern blot and cosmid cloning established single-copy loci for both genes within the MHC class III region.","method":"Cosmid library screening, Southern blot analysis of genomic DNA, restriction enzyme mapping","journal":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct genomic mapping by Southern blot and cosmid cloning, replicated by multiple labs","pmids":["6149579","3902623"],"is_preprint":false},{"year":1985,"finding":"gamma-Interferon (IFN-γ) increases C2 and Factor B synthesis in human monocytes and in murine fibroblasts transfected with human C2 and Factor B genes; this regulation is pretranslational and does not require new protein synthesis, establishing that IFN-γ regulates C2 expression at the mRNA level.","method":"Metabolic labeling, mRNA quantification, transfected L-cell expression system, cycloheximide block experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — pretranslational regulation established in two independent cell systems (primary monocytes and transfected fibroblasts) with multiple orthogonal methods","pmids":["2866182"],"is_preprint":false},{"year":1985,"finding":"Cosmid DNA bearing the human C2 and Factor B genes, when transfected into mouse L cells, directed synthesis and secretion of biologically active human C2 (as distinct from endogenous L-cell C2), demonstrating the C2 gene is sufficient for expression of hemolytically active protein in a heterologous cell type.","method":"DNA-mediated gene transfer into mouse L cells, hemolytic assay, RNA analysis, immunological assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reconstitution in transfected cells with hemolytic activity readout, single lab","pmids":["3850903"],"is_preprint":false},{"year":2002,"finding":"The Schistosoma parasite complement C2 receptor inhibitor trispanning (CRIT) binds human C2 via the C2a segment and directly competes with C4b for binding to C2, thereby inhibiting classical pathway C3 convertase formation; the C-terminal 11-amino-acid peptide H17 of CRIT-ed1 is sufficient for this inhibition, and the homologous C4 beta-chain region F222–Y232 shares the same C2-binding function.","method":"Complement hemolytic inhibition assays, peptide competition experiments, antibody cross-reactivity studies","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional inhibition assays with peptide competition and antibody cross-reactivity, single lab, two orthogonal approaches","pmids":["11994478"],"is_preprint":false},{"year":1999,"finding":"In vivo experiments in C2-deficient guinea pigs demonstrated that a C2-bypass pathway of complement activation can produce tissue damage; both the classical and alternative pathways are required for this bypass, and blocking either pathway with sCR1 or EGTA-Mg2+ inhibited lysis and prevented Forssman shock in C2-deficient animals.","method":"In vivo Forssman shock model with C2-deficient guinea pigs, complement inhibitor treatments (sCR1, EGTA-Mg2+, heat inactivation), in vitro hemolytic assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model combined with multiple pharmacological pathway-specific inhibitors and in vitro confirmation","pmids":["10477630"],"is_preprint":false},{"year":2020,"finding":"ARGX-117, a humanized monoclonal antibody targeting the Sushi-2 domain of complement C2, prevents formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3; it does not inhibit the alternative pathway and dose-dependently reduces free C2 levels and classical pathway activity in cynomolgus monkeys.","method":"Mode-of-action binding characterization, in vitro complement cytotoxicity assays (autoimmune hemolytic anemia and antibody-mediated rejection models), PK/PD study in cynomolgus monkeys","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic binding to defined domain (Sushi-2) combined with in vitro functional assays and in vivo primate pharmacodynamics","pmids":["32926878"],"is_preprint":false},{"year":2013,"finding":"siRNA-mediated suppression of C2 expression in vivo (in EAMG mice) significantly reduced C2 mRNA in blood cells and liver, reduced C3 and membrane-attack complex deposition at neuromuscular junctions, improved muscle strength, and preserved acetylcholine receptor levels, establishing C2 as a critical node in classical pathway-mediated pathology of experimental myasthenia gravis.","method":"In vivo siRNA knockdown, mRNA quantification, immunofluorescence of neuromuscular junction complement deposition, functional muscle strength assessment","journal":"Journal of autoimmunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD with defined molecular and functional readouts, single lab","pmids":["23410585"],"is_preprint":false},{"year":1994,"finding":"A 28-base pair deletion in exon 6 of the C2 gene (type I C2 deficiency) was identified as the most common molecular cause of C2 deficiency and found significantly more frequently in Caucasoid SLE patients compared to controls; this mutation is linked to the HLA haplotype DRB1*1501.","method":"PCR amplification and gel electrophoresis-based genotyping of C2 exon 6 deletion in SLE patients and controls","journal":"The Journal of rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular identification of causative mutation with population-level validation, single method","pmids":["7932427"],"is_preprint":false},{"year":1986,"finding":"Three DNA restriction fragment length polymorphisms were identified within the C2 gene by Southern blot analysis, which subdivide the common C2C allele and reveal substantially greater variability at the C2 locus than previously detectable by protein typing alone.","method":"Southern blot analysis of genomic restriction digests","journal":"Immunological reviews","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genomic mapping with Southern blot, single lab","pmids":["3902623"],"is_preprint":false}],"current_model":"Human complement C2 is a serine protease encoded by a single gene in the MHC class III region, adjacent to Factor B; it functions as the catalytic subunit (C2a fragment) of the classical and lectin pathway C3 convertase (C4b2a), its expression is upregulated pretranslationally by IFN-γ in monocytes, its Sushi-2 domain mediates binding to C4b to form the proconvertase, and loss-of-function (most commonly a 28-bp exon-6 deletion) impairs classical pathway activation and predisposes to bacterial infections and autoimmune disease."},"narrative":{"mechanistic_narrative":"Complement C2 is a serine protease that supplies the catalytic activity of the classical and lectin pathway C3 convertase, positioning it as a central node in antibody- and lectin-triggered complement activation [PMID:6149575, PMID:6149579, PMID:23410585]. The cloned cDNA encodes a 732-residue secreted polypeptide whose recombinant product is antigenically and hemolytically indistinguishable from serum C2, confirming the gene is sufficient to specify the functional protein [PMID:2493504, PMID:3850903]. C2 and Factor B are homologous proteases encoded by adjacent single-copy loci in the MHC class III region; the C2 catalytic chain carries the convertase active site while its non-catalytic chain is built from three complement-control-protein (Sushi) repeats [PMID:6149575, PMID:6149579, PMID:3902623]. Assembly of the proconvertase requires C2 binding to C4b: the Sushi-2 domain mediates this interaction, and antibody (ARGX-117) blockade of Sushi-2 prevents proconvertase formation and abrogates classical and lectin — but not alternative — pathway activation upstream of C3 [PMID:32926878]. The C2a segment is also the docking site exploited by the parasite inhibitor CRIT, which competes with C4b for C2 [PMID:11994478]. C2 expression is regulated pretranslationally, being upregulated by IFN-γ in monocytes and transfected fibroblasts at the mRNA level without requiring new protein synthesis [PMID:2866182]. C2 is a critical effector in complement-mediated tissue injury, since its in vivo knockdown reduces C3 and membrane-attack-complex deposition and disease severity in experimental myasthenia gravis [PMID:23410585], and a common 28-bp exon-6 deletion causes type I C2 deficiency that is enriched in SLE patients [PMID:7932427].","teleology":[{"year":1984,"claim":"Establishing that C2 carries the catalytic site of the classical pathway C3 convertase and is structurally a serine protease defined its core enzymatic role and its evolutionary kinship with Factor B.","evidence":"CNBr peptide amino acid sequencing and biochemical convertase characterization, plus genomic Southern blot and cosmid mapping of the MHC class III locus","pmids":["6149575","6149579","3902623"],"confidence":"High","gaps":["Did not resolve the structural basis of C4b recognition","Catalytic mechanism on C3 substrate not detailed at residue level"]},{"year":1985,"claim":"Demonstrating IFN-γ-driven, cycloheximide-independent increases in C2 synthesis showed the gene is controlled pretranslationally at the mRNA level, linking C2 production to immune activation signals.","evidence":"Metabolic labeling, mRNA quantification and cycloheximide block in primary monocytes and transfected L cells","pmids":["2866182","3850903"],"confidence":"High","gaps":["Promoter/enhancer elements and transcription factors mediating IFN-γ response not identified","Did not distinguish transcriptional rate from mRNA stability effects"]},{"year":1989,"claim":"Cloning the full-length cDNA and reconstituting a hemolytically active secreted protein confirmed that the single C2 transcript encodes the complete functional protease.","evidence":"cDNA cloning with COS cell expression, Western blot and hemolytic activity assay","pmids":["2493504"],"confidence":"High","gaps":["No structural model of the mature protein","Post-translational cleavage to C2a/C2b not mechanistically dissected here"]},{"year":1994,"claim":"Identifying the 28-bp exon-6 deletion as the most common cause of type I C2 deficiency and its enrichment in SLE connected C2 loss-of-function to autoimmune disease.","evidence":"PCR genotyping of the exon-6 deletion in SLE patients versus controls","pmids":["7932427"],"confidence":"Medium","gaps":["Association is genetic/population-level, not a direct causal mechanism for SLE","HLA-DRB1*1501 linkage confounds attribution to C2 alone"]},{"year":1999,"claim":"Showing that complement-mediated tissue damage can proceed via a C2-bypass requiring both classical and alternative pathways clarified the pathway dependencies around C2 in vivo.","evidence":"Forssman shock model in C2-deficient guinea pigs with pathway-specific inhibitors (sCR1, EGTA-Mg2+) and in vitro hemolysis","pmids":["10477630"],"confidence":"High","gaps":["Molecular identity of the bypass convertase not defined","Relevance of the bypass to human C2 deficiency unresolved"]},{"year":2002,"claim":"Mapping the parasite inhibitor CRIT to the C2a segment, where it competes with C4b, localized the C4b-binding interface and revealed a host-mimicry inhibition strategy.","evidence":"Hemolytic inhibition and peptide competition assays with antibody cross-reactivity","pmids":["11994478"],"confidence":"Medium","gaps":["Structural detail of the CRIT/C4b shared epitope not solved","Physiological relevance to immune evasion in infection not established"]},{"year":2013,"claim":"In vivo siRNA knockdown showing reduced complement deposition, preserved acetylcholine receptors and improved muscle strength established C2 as a tractable effector node in classical-pathway autoimmune pathology.","evidence":"In vivo siRNA knockdown in EAMG mice with mRNA, NMJ complement immunofluorescence and muscle strength readouts","pmids":["23410585"],"confidence":"Medium","gaps":["Single-lab study","Did not separate liver-derived from local C2 contributions to pathology"]},{"year":2020,"claim":"Defining the ARGX-117 epitope on the Sushi-2 domain pinpointed the C4b-binding region required for proconvertase assembly and validated upstream pathway-selective C2 inhibition.","evidence":"Antibody mode-of-action binding, in vitro cytotoxicity assays and PK/PD in cynomolgus monkeys","pmids":["32926878"],"confidence":"High","gaps":["No high-resolution structure of the C2 Sushi-2/C4b complex","Lectin-pathway-specific contributions not separated from classical pathway in vivo"]},{"year":null,"claim":"The atomic structure of C2 bound to C4b and the residue-level mechanism of C3 substrate cleavage by the C4b2a convertase remain undefined in this corpus.","evidence":"","pmids":[],"confidence":"High","gaps":["No experimental structure of the proconvertase or active convertase","Catalytic mechanism and substrate specificity determinants uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,6,7]}],"complexes":["C4b2a C3 convertase (classical/lectin pathway)"],"partners":["C4B","CFB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P06681","full_name":"Complement C2","aliases":["C3/C5 convertase"],"length_aa":752,"mass_kda":83.3,"function":"Precursor of the catalytic component of the C3 and C5 convertase complexes, which are part of the complement pathway, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:39914456, PubMed:39814882). Component C2 is part of the classical, lectin and GZMK complement systems (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:22691502, PubMed:39914456) Catalytic component of the complement C3 and C5 convertase complexes (PubMed:12878586, PubMed:17027507, PubMed:18204047, PubMed:6906228). Following complement activation, recruited to the surface of pathogens by complement C4b opsonin to form the C3 convertase, or C3b and C4b opsonins to form the C5 convertase (PubMed:6611150, PubMed:6906228). As part of the C3 convertase, cleaves and activate C3 into C3a anaphylatoxin and C3b opsonin, the next components of the complement pathways (PubMed:14561755, PubMed:17027507). As part of the C5 convertase, cleaves and activate C5 into C5a anaphylatoxin and C5b component of the membrane attack complex (PubMed:12878586, PubMed:17027507, PubMed:18204047)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P06681/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C2","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/C2","total_profiled":1310},"omim":[{"mim_id":"621518","title":"SYNAPTOTAGMIN 17; SYT17","url":"https://www.omim.org/entry/621518"},{"mim_id":"621499","title":"CRANIOSYNOSTOSIS-SCOLIOSIS SYNDROME; CRSS","url":"https://www.omim.org/entry/621499"},{"mim_id":"621370","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 9; XKR9","url":"https://www.omim.org/entry/621370"},{"mim_id":"621368","title":"X KELL BLOOD GROUP PRECURSOR-RELATED FAMILY, MEMBER 4; XKR4","url":"https://www.omim.org/entry/621368"},{"mim_id":"621206","title":"TRANSMEMBRANE AND IMMUNOGLOBULIN DOMAINS-CONTAINING PROTEIN 1; TMIGD1","url":"https://www.omim.org/entry/621206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":454.7}],"url":"https://www.proteinatlas.org/search/C2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P06681","domains":[{"cath_id":"2.10.70.10","chopping":"33-85","consensus_level":"high","plddt":82.8091,"start":33,"end":85},{"cath_id":"2.10.70.10","chopping":"97-209","consensus_level":"high","plddt":91.3939,"start":97,"end":209},{"cath_id":"3.40.50.410","chopping":"244-453","consensus_level":"high","plddt":91.171,"start":244,"end":453},{"cath_id":"2.40.10.120","chopping":"473-705_713-743","consensus_level":"medium","plddt":94.0829,"start":473,"end":743}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P06681","model_url":"https://alphafold.ebi.ac.uk/files/AF-P06681-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P06681-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C2","jax_strain_url":"https://www.jax.org/strain/search?query=C2"},"sequence":{"accession":"P06681","fasta_url":"https://rest.uniprot.org/uniprotkb/P06681.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P06681/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P06681"}},"corpus_meta":[{"pmid":"8976547","id":"PMC_8976547","title":"The C2 domain calcium-binding motif: structural and functional diversity.","date":"1996","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/8976547","citation_count":711,"is_preprint":false},{"pmid":"3736664","id":"PMC_3736664","title":"Botulinum C2 toxin ADP-ribosylates actin.","date":"1986","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/3736664","citation_count":435,"is_preprint":false},{"pmid":"17719543","id":"PMC_17719543","title":"Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/17719543","citation_count":233,"is_preprint":false},{"pmid":"2858498","id":"PMC_2858498","title":"Rat medulla oblongata. 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Adrenergic (C1 and C2) neurons, nerve fibers and presumptive terminal processes.","date":"1985","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/2858498","citation_count":195,"is_preprint":false},{"pmid":"6785232","id":"PMC_6785232","title":"Purification and characterization of two components of botulinum C2 toxin.","date":"1980","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/6785232","citation_count":191,"is_preprint":false},{"pmid":"24440424","id":"PMC_24440424","title":"Signaling through C2 domains: more than one lipid target.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24440424","citation_count":180,"is_preprint":false},{"pmid":"11959863","id":"PMC_11959863","title":"Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11959863","citation_count":168,"is_preprint":false},{"pmid":"19232397","id":"PMC_19232397","title":"Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19232397","citation_count":165,"is_preprint":false},{"pmid":"11156408","id":"PMC_11156408","title":"Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor.","date":"2000","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/11156408","citation_count":151,"is_preprint":false},{"pmid":"2866182","id":"PMC_2866182","title":"gamma-Interferon increases expression of class III complement genes C2 and factor B in human monocytes and in murine fibroblasts transfected with human C2 and factor B genes.","date":"1985","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2866182","citation_count":132,"is_preprint":false},{"pmid":"4578155","id":"PMC_4578155","title":"C2 deficiency. 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genetics.","date":"1986","source":"Biochemical Society symposium","url":"https://pubmed.ncbi.nlm.nih.gov/3101701","citation_count":16,"is_preprint":false},{"pmid":"25904865","id":"PMC_25904865","title":"Voltage-sensing phosphatase modulation by a C2 domain.","date":"2015","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25904865","citation_count":16,"is_preprint":false},{"pmid":"37462428","id":"PMC_37462428","title":"Chemoselective Late-Stage Functionalization of Peptides via Photocatalytic C2-Alkylation of Tryptophan.","date":"2023","source":"Organic letters","url":"https://pubmed.ncbi.nlm.nih.gov/37462428","citation_count":16,"is_preprint":false},{"pmid":"6149575","id":"PMC_6149575","title":"Structure and activation of complement components C2 and factor B.","date":"1984","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/6149575","citation_count":16,"is_preprint":false},{"pmid":"23999003","id":"PMC_23999003","title":"SYT14L, especially its C2 domain, is involved in regulating melanocyte differentiation.","date":"2013","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/23999003","citation_count":14,"is_preprint":false},{"pmid":"1697576","id":"PMC_1697576","title":"Sequence analysis and transcriptional organization of the Rhodopseudomonas viridis cytochrome c2 gene.","date":"1990","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1697576","citation_count":14,"is_preprint":false},{"pmid":"18849467","id":"PMC_18849467","title":"C2 domain protein MIN1 promotes eyespot organization in Chlamydomonas reinhardtii.","date":"2008","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/18849467","citation_count":14,"is_preprint":false},{"pmid":"28192161","id":"PMC_28192161","title":"Enzymatic cleavage of myoferlin releases a dual C2-domain module linked to ERK signalling.","date":"2017","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/28192161","citation_count":14,"is_preprint":false},{"pmid":"39269903","id":"PMC_39269903","title":"Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39269903","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45359,"output_tokens":2844,"usd":0.089369,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9843,"output_tokens":2808,"usd":0.059707,"stage2_stop_reason":"end_turn"},"total_usd":0.149076,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify which papers are about the human complement component C2 (the gene queried) versus other proteins/genes that happen to use \"C2\" in their name (C2 domains, botulinum C2 toxin, ceramide C2, myoblast cell line C2, apolipoprotein C2, phage c2, etc.).\n\nThe canonical human complement C2 gene encodes the second component of the complement system, a serine protease that forms part of the classical and lectin pathway C3 convertase (C4b2a). Relevant papers: PMID 37, 95, 92, 27, 56, 10, 48, 51, 52, 85, 83, 35, 11, 17, 36.\n\nPapers about C2 domains (generic), botulinum C2 toxin, ceramide analogs, cell lines named C2, apolipoprotein C2, phage P22 c2 repressor, bacterial cytochrome c2, etc. are NOT about human complement C2 and should be excluded.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"Full-length cDNA cloning of human complement C2 revealed a 732-amino acid mature polypeptide with a signal peptide; transfection of the cDNA into COS cells produced a secreted protein with antigenicity and hemolytic activity indistinguishable from native serum C2, confirming the cDNA encodes the functional protein.\",\n      \"method\": \"cDNA cloning, COS cell expression, Western blot, hemolytic activity assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of functional protein from cloned cDNA with hemolytic activity validation and Western blot in a single rigorous study\",\n      \"pmids\": [\"2493504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"C2 and Factor B are homologous serine proteases encoded by adjacent single-copy loci in the MHC class III region; C2 contains the catalytic site of the classical pathway C3 convertase (C4b2a), and both proteins share structural homology in their catalytic chains while their non-catalytic chains contain three tandem complement-control-protein repeats.\",\n      \"method\": \"Amino acid sequencing of CNBr peptides, protein homology analysis, biochemical characterization of convertase activity\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical sequencing and functional characterization replicated across multiple labs\",\n      \"pmids\": [\"6149575\", \"6149579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1984,\n      \"finding\": \"The C2 gene spans approximately 18 kb of DNA and lies less than 500 bp from the Factor B gene on chromosome 6; genomic Southern blot and cosmid cloning established single-copy loci for both genes within the MHC class III region.\",\n      \"method\": \"Cosmid library screening, Southern blot analysis of genomic DNA, restriction enzyme mapping\",\n      \"journal\": \"Philosophical transactions of the Royal Society of London. Series B, Biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct genomic mapping by Southern blot and cosmid cloning, replicated by multiple labs\",\n      \"pmids\": [\"6149579\", \"3902623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"gamma-Interferon (IFN-γ) increases C2 and Factor B synthesis in human monocytes and in murine fibroblasts transfected with human C2 and Factor B genes; this regulation is pretranslational and does not require new protein synthesis, establishing that IFN-γ regulates C2 expression at the mRNA level.\",\n      \"method\": \"Metabolic labeling, mRNA quantification, transfected L-cell expression system, cycloheximide block experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pretranslational regulation established in two independent cell systems (primary monocytes and transfected fibroblasts) with multiple orthogonal methods\",\n      \"pmids\": [\"2866182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"Cosmid DNA bearing the human C2 and Factor B genes, when transfected into mouse L cells, directed synthesis and secretion of biologically active human C2 (as distinct from endogenous L-cell C2), demonstrating the C2 gene is sufficient for expression of hemolytically active protein in a heterologous cell type.\",\n      \"method\": \"DNA-mediated gene transfer into mouse L cells, hemolytic assay, RNA analysis, immunological assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reconstitution in transfected cells with hemolytic activity readout, single lab\",\n      \"pmids\": [\"3850903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Schistosoma parasite complement C2 receptor inhibitor trispanning (CRIT) binds human C2 via the C2a segment and directly competes with C4b for binding to C2, thereby inhibiting classical pathway C3 convertase formation; the C-terminal 11-amino-acid peptide H17 of CRIT-ed1 is sufficient for this inhibition, and the homologous C4 beta-chain region F222–Y232 shares the same C2-binding function.\",\n      \"method\": \"Complement hemolytic inhibition assays, peptide competition experiments, antibody cross-reactivity studies\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional inhibition assays with peptide competition and antibody cross-reactivity, single lab, two orthogonal approaches\",\n      \"pmids\": [\"11994478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"In vivo experiments in C2-deficient guinea pigs demonstrated that a C2-bypass pathway of complement activation can produce tissue damage; both the classical and alternative pathways are required for this bypass, and blocking either pathway with sCR1 or EGTA-Mg2+ inhibited lysis and prevented Forssman shock in C2-deficient animals.\",\n      \"method\": \"In vivo Forssman shock model with C2-deficient guinea pigs, complement inhibitor treatments (sCR1, EGTA-Mg2+, heat inactivation), in vitro hemolytic assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model combined with multiple pharmacological pathway-specific inhibitors and in vitro confirmation\",\n      \"pmids\": [\"10477630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARGX-117, a humanized monoclonal antibody targeting the Sushi-2 domain of complement C2, prevents formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3; it does not inhibit the alternative pathway and dose-dependently reduces free C2 levels and classical pathway activity in cynomolgus monkeys.\",\n      \"method\": \"Mode-of-action binding characterization, in vitro complement cytotoxicity assays (autoimmune hemolytic anemia and antibody-mediated rejection models), PK/PD study in cynomolgus monkeys\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic binding to defined domain (Sushi-2) combined with in vitro functional assays and in vivo primate pharmacodynamics\",\n      \"pmids\": [\"32926878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"siRNA-mediated suppression of C2 expression in vivo (in EAMG mice) significantly reduced C2 mRNA in blood cells and liver, reduced C3 and membrane-attack complex deposition at neuromuscular junctions, improved muscle strength, and preserved acetylcholine receptor levels, establishing C2 as a critical node in classical pathway-mediated pathology of experimental myasthenia gravis.\",\n      \"method\": \"In vivo siRNA knockdown, mRNA quantification, immunofluorescence of neuromuscular junction complement deposition, functional muscle strength assessment\",\n      \"journal\": \"Journal of autoimmunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD with defined molecular and functional readouts, single lab\",\n      \"pmids\": [\"23410585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A 28-base pair deletion in exon 6 of the C2 gene (type I C2 deficiency) was identified as the most common molecular cause of C2 deficiency and found significantly more frequently in Caucasoid SLE patients compared to controls; this mutation is linked to the HLA haplotype DRB1*1501.\",\n      \"method\": \"PCR amplification and gel electrophoresis-based genotyping of C2 exon 6 deletion in SLE patients and controls\",\n      \"journal\": \"The Journal of rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular identification of causative mutation with population-level validation, single method\",\n      \"pmids\": [\"7932427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Three DNA restriction fragment length polymorphisms were identified within the C2 gene by Southern blot analysis, which subdivide the common C2C allele and reveal substantially greater variability at the C2 locus than previously detectable by protein typing alone.\",\n      \"method\": \"Southern blot analysis of genomic restriction digests\",\n      \"journal\": \"Immunological reviews\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genomic mapping with Southern blot, single lab\",\n      \"pmids\": [\"3902623\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human complement C2 is a serine protease encoded by a single gene in the MHC class III region, adjacent to Factor B; it functions as the catalytic subunit (C2a fragment) of the classical and lectin pathway C3 convertase (C4b2a), its expression is upregulated pretranslationally by IFN-γ in monocytes, its Sushi-2 domain mediates binding to C4b to form the proconvertase, and loss-of-function (most commonly a 28-bp exon-6 deletion) impairs classical pathway activation and predisposes to bacterial infections and autoimmune disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Complement C2 is a serine protease that supplies the catalytic activity of the classical and lectin pathway C3 convertase, positioning it as a central node in antibody- and lectin-triggered complement activation [#1, #8]. The cloned cDNA encodes a 732-residue secreted polypeptide whose recombinant product is antigenically and hemolytically indistinguishable from serum C2, confirming the gene is sufficient to specify the functional protein [#0, #4]. C2 and Factor B are homologous proteases encoded by adjacent single-copy loci in the MHC class III region; the C2 catalytic chain carries the convertase active site while its non-catalytic chain is built from three complement-control-protein (Sushi) repeats [#1, #2]. Assembly of the proconvertase requires C2 binding to C4b: the Sushi-2 domain mediates this interaction, and antibody (ARGX-117) blockade of Sushi-2 prevents proconvertase formation and abrogates classical and lectin — but not alternative — pathway activation upstream of C3 [#7]. The C2a segment is also the docking site exploited by the parasite inhibitor CRIT, which competes with C4b for C2 [#5]. C2 expression is regulated pretranslationally, being upregulated by IFN-\\u03b3 in monocytes and transfected fibroblasts at the mRNA level without requiring new protein synthesis [#3]. C2 is a critical effector in complement-mediated tissue injury, since its in vivo knockdown reduces C3 and membrane-attack-complex deposition and disease severity in experimental myasthenia gravis [#8], and a common 28-bp exon-6 deletion causes type I C2 deficiency that is enriched in SLE patients [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 1984,\n      \"claim\": \"Establishing that C2 carries the catalytic site of the classical pathway C3 convertase and is structurally a serine protease defined its core enzymatic role and its evolutionary kinship with Factor B.\",\n      \"evidence\": \"CNBr peptide amino acid sequencing and biochemical convertase characterization, plus genomic Southern blot and cosmid mapping of the MHC class III locus\",\n      \"pmids\": [\"6149575\", \"6149579\", \"3902623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of C4b recognition\", \"Catalytic mechanism on C3 substrate not detailed at residue level\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Demonstrating IFN-\\u03b3-driven, cycloheximide-independent increases in C2 synthesis showed the gene is controlled pretranslationally at the mRNA level, linking C2 production to immune activation signals.\",\n      \"evidence\": \"Metabolic labeling, mRNA quantification and cycloheximide block in primary monocytes and transfected L cells\",\n      \"pmids\": [\"2866182\", \"3850903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter/enhancer elements and transcription factors mediating IFN-\\u03b3 response not identified\", \"Did not distinguish transcriptional rate from mRNA stability effects\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Cloning the full-length cDNA and reconstituting a hemolytically active secreted protein confirmed that the single C2 transcript encodes the complete functional protease.\",\n      \"evidence\": \"cDNA cloning with COS cell expression, Western blot and hemolytic activity assay\",\n      \"pmids\": [\"2493504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the mature protein\", \"Post-translational cleavage to C2a/C2b not mechanistically dissected here\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Identifying the 28-bp exon-6 deletion as the most common cause of type I C2 deficiency and its enrichment in SLE connected C2 loss-of-function to autoimmune disease.\",\n      \"evidence\": \"PCR genotyping of the exon-6 deletion in SLE patients versus controls\",\n      \"pmids\": [\"7932427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Association is genetic/population-level, not a direct causal mechanism for SLE\", \"HLA-DRB1*1501 linkage confounds attribution to C2 alone\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showing that complement-mediated tissue damage can proceed via a C2-bypass requiring both classical and alternative pathways clarified the pathway dependencies around C2 in vivo.\",\n      \"evidence\": \"Forssman shock model in C2-deficient guinea pigs with pathway-specific inhibitors (sCR1, EGTA-Mg2+) and in vitro hemolysis\",\n      \"pmids\": [\"10477630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the bypass convertase not defined\", \"Relevance of the bypass to human C2 deficiency unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping the parasite inhibitor CRIT to the C2a segment, where it competes with C4b, localized the C4b-binding interface and revealed a host-mimicry inhibition strategy.\",\n      \"evidence\": \"Hemolytic inhibition and peptide competition assays with antibody cross-reactivity\",\n      \"pmids\": [\"11994478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the CRIT/C4b shared epitope not solved\", \"Physiological relevance to immune evasion in infection not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"In vivo siRNA knockdown showing reduced complement deposition, preserved acetylcholine receptors and improved muscle strength established C2 as a tractable effector node in classical-pathway autoimmune pathology.\",\n      \"evidence\": \"In vivo siRNA knockdown in EAMG mice with mRNA, NMJ complement immunofluorescence and muscle strength readouts\",\n      \"pmids\": [\"23410585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Did not separate liver-derived from local C2 contributions to pathology\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining the ARGX-117 epitope on the Sushi-2 domain pinpointed the C4b-binding region required for proconvertase assembly and validated upstream pathway-selective C2 inhibition.\",\n      \"evidence\": \"Antibody mode-of-action binding, in vitro cytotoxicity assays and PK/PD in cynomolgus monkeys\",\n      \"pmids\": [\"32926878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the C2 Sushi-2/C4b complex\", \"Lectin-pathway-specific contributions not separated from classical pathway in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic structure of C2 bound to C4b and the residue-level mechanism of C3 substrate cleavage by the C4b2a convertase remain undefined in this corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of the proconvertase or active convertase\", \"Catalytic mechanism and substrate specificity determinants uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 6, 7]}\n    ],\n    \"complexes\": [\"C4b2a C3 convertase (classical/lectin pathway)\"],\n    \"partners\": [\"C4B\", \"CFB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}