{"gene":"C7","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":1988,"finding":"Human complement C7 is a single-chain glycoprotein of 821 amino acids with 28 disulfide bonds, organized as a mosaic protein with N-terminal homology to C8 and C9 and C-terminal cysteine-rich domains homologous to LDL receptor, EGF precursor, thrombospondin, and coagulation factors IX/X. Electron microscopy revealed a flexible elongated molecule; in the C5b-7 complex, C7 forms the stalk region that mediates hydrophilic-to-amphiphilic transition and membrane anchoring, with photoreactive cross-linking confirming that C6 and C7 constitute the membrane-anchoring stalk of the C5b-7 complex.","method":"cDNA sequencing, circular dichroism, transmission electron microscopy, photoreactive cross-linking with radioiodinated phosphatidylethanolamine","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — primary structure from cDNA, EM structure of complex, direct cross-linking to identify membrane-binding domain; multiple orthogonal methods in single study","pmids":["3335508"],"is_preprint":false},{"year":1979,"finding":"C6 and C7 are structurally very similar single-chain glycoproteins with nearly identical amino acid compositions, molecular weights (~120–125 kDa), electrophoretic properties (both β2-globulins), and secondary structure content, consistent with evolution from a common ancestral gene.","method":"Affinity chromatography purification, amino acid composition analysis, SDS-PAGE, isoelectric focusing, UV and CD spectroscopy","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical characterizations of purified proteins","pmids":["381516"],"is_preprint":false},{"year":1993,"finding":"Clusterin (apolipoprotein J/complement inhibitor) binds specifically to complement C7, C8β, and the C9b fragment of C9 (which contains the hydrophobic membrane interaction segment). Binding to C9 is competed by polymerized C9 but not by C6, C7, or CD59, indicating that conformational changes during the hydrophilic-amphiphilic transition of C9 expose the clusterin interaction site. Both subunits of clusterin interact with C9 and equivalently inhibit C5b-9 hemolysis and zinc-induced C9 polymerization.","method":"Ligand blotting with [125I]clusterin, competition binding assays, hemolysis inhibition assays, C9 polymerization assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct radioligand binding with competition, functional hemolysis assays, multiple orthogonal approaches","pmids":["8345200"],"is_preprint":false},{"year":1995,"finding":"Complement component C7 (but not C5b6, C8, or C9) is a plasminogen-binding protein. C7, both in isolated form and after incorporation into the C5b-9 terminal complement complex, binds plasminogen via lysine-binding sites (inhibited by 6-aminohexanoic acid and tranexamic acid). Tissue-type plasminogen activator (tPA)-mediated plasminogen activation is enhanced in the presence of C7, suggesting C7 focuses plasmin activity to complement-tagged structures.","method":"Radioligand binding studies with [125I]-plasminogen, competition assays with lysine analogues, tPA-mediated plasminogen activation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — direct radioligand binding, mechanistic competition experiments, functional plasmin activation assay","pmids":["7814888"],"is_preprint":false},{"year":1975,"finding":"A C7-inactivating principle was identified in C7-deficient human serum that can inactivate C7 both in fluid phase and in its cell-bound state, suggesting existence of a physiological regulator of C7 activity.","method":"Functional complement hemolysis assays, immunodiffusion, physicochemical characterization of inactivator","journal":"Clinical and experimental immunology","confidence":"Low","confidence_rationale":"Tier 3 — single study, functional assay without molecular identity of inactivator","pmids":["813921"],"is_preprint":false},{"year":1985,"finding":"In paroxysmal nocturnal hemoglobinuria (PNH) type III erythrocytes, enhanced reactive lysis by C5b-9 is not due to increased C7 binding from fluid phase; C5b6-dependent 125I-C7 binding to PNH erythrocytes is equivalent to normal erythrocytes. Instead, the increased lysis reflects more efficient conversion of cell-bound C5b67 to hemolytic sites on PNH cells, indicating a post-C7 binding defect downstream in MAC assembly. Pre-incubation with anti-C3 antibodies failed to inhibit PNH reactive lysis, ruling out cell-bound C3b as the mechanism.","method":"125I-C7 radioligand binding assays, reactive lysis hemolysis assays, anti-C3 antibody inhibition experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct quantitative radioligand binding with multiple controls establishing post-C7 mechanism; single study","pmids":["3964820"],"is_preprint":false},{"year":1986,"finding":"Human monocytes cultured under serum-free conditions synthesize and secrete complement components C5, C6, C7, C8, and C9, which assemble as a functional terminal complement complex on activator surfaces (agarose beads), as demonstrated by binding of antibodies against C5–C9 and a neoepitope of polymerized C9.","method":"Serum-free monocyte culture, immunoassay with anti-complement antibodies (including anti-polymerized C9 neoantigen), alternative pathway activation on agarose beads","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — serum-free culture eliminates serum contamination; functional MAC assembly demonstrated; single study","pmids":["3764345"],"is_preprint":false},{"year":1990,"finding":"Human fibroblasts produce complement components C3, C5, C6, C7, C8, and C9 in vitro, and the locally synthesized terminal components assemble into a functional terminal complement complex on alternative pathway activator surfaces, as evidenced by anti-activated C9 neoepitope reactivity.","method":"Serum-free co-culture of fibroblasts with agarose activators, radioimmunoassay with anti-complement antibodies including anti-C9 neoepitope","journal":"Scandinavian journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — serum-free system; neoepitope detection confirms MAC assembly; single study","pmids":["2270435"],"is_preprint":false},{"year":1995,"finding":"Human polymorphonuclear leukocytes (PMNs) store large quantities of C7 and C6 intracellularly (median 149.7 ng and 60.1 ng per 10^7 cells respectively), independent of serum uptake, with C7 and C6 release occurring upon PMA stimulation. The stored C7 retains molecular integrity (identical MW to serum C7) and functional activity, being incorporated into the terminal complement complex.","method":"ELISA, immunoblot, allotype tracking experiment (C7 M/N allotype), PMA stimulation of PMNs, terminal complement complex functional assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — allotype experiment rules out serum uptake; functional MAC incorporation demonstrated; single study","pmids":["7722325"],"is_preprint":false},{"year":1996,"finding":"The majority of circulating C7 is synthesized by the liver and bone marrow. Following organ transplantation with C7 allotype mismatch, liver transplants contributed 30–62% of circulating C7, and a bone marrow transplant contributed 18–27% during post-transplant inflammation, demonstrating organ-specific origins of plasma C7.","method":"C7 allotype-specific ELISA (monoclonal antibody WU 4-15) in bone marrow and liver transplant recipients with allotype mismatch","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — natural allotype tracing in transplant patients provides direct evidence of synthesis sites; limited patient numbers","pmids":["8814254"],"is_preprint":false},{"year":1997,"finding":"C7 deficiency is caused by diverse molecular defects. In Irish families, mutations include a heterozygous 3' splice acceptor site mutation in intron 1 and a deletion of exons 7 and 8. In Israeli families of Moroccan Sephardic Jewish origin, a missense mutation in exon 9 (shared haplotype, likely ancient) causes the deficiency. These mutations result in absent or severely reduced circulating C7 protein.","method":"Exon PCR and direct sequencing, Southern blotting, haplotype marker analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct sequencing of multiple mutations; population haplotype analysis confirms founder effects; single study","pmids":["9218625"],"is_preprint":false},{"year":2007,"finding":"The C7 R499S missense mutation causes subtotal C7 deficiency (C7SD) by producing a misfolded protein that is retained in the endoplasmic reticulum, while wild-type C7 localizes to the Golgi apparatus. R499S represents a loss-of-function polymorphism with a frequency of ~1% in normal Caucasian populations, occurring in compound heterozygosity with complete C7 null alleles.","method":"Exon-specific PCR and sequencing, subcellular localization by immunofluorescence (ER vs. Golgi markers), population frequency analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — direct sequencing plus subcellular localization experiments establish mechanism of ER retention; replicated across multiple families","pmids":["17407100"],"is_preprint":false},{"year":1999,"finding":"Phylogenetic analysis of terminal complement complex proteins (C6, C7, C8α, C8β, C9) demonstrates that they all originate from a single ancestral gene with complex modular composition, with C6 and C7 being the earliest diverged members. Evolution involved gene duplications and module loss, resulting in successive proteins with decreasing modular complexity; C9 and perforin represent parallel evolution toward pore-forming function.","method":"Phylogenetic analysis of amino acid sequences using all available C6–C9 and perforin sequences","journal":"Journal of molecular evolution","confidence":"Medium","confidence_rationale":"Tier 4 — computational phylogenetic analysis only; replicated finding consistent with biochemical data from other studies","pmids":["10441679"],"is_preprint":false},{"year":2015,"finding":"C7 and complement factor H (CFH) are required to maintain stemness in liver tumor-initiating cells. Knockdown of C7 or CFH abrogates tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo tumor growth. Mechanistically, C7 and CFH regulate LSF-1 expression, which directly controls transcription of stemness factors.","method":"NanoString gene expression analysis of tumorspheres, siRNA knockdown, overexpression studies, tumorsphere formation assay, in vivo xenograft assay, LSF-1 interaction analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function and gain-of-function with specific cellular phenotype readout; pathway placement via LSF-1; single lab study","pmids":["26723877"],"is_preprint":false},{"year":2018,"finding":"A rare missense variant p.K420Q in the C7 gene is associated with Alzheimer's disease in Han Chinese. Overexpression of mutant C7 (K420Q) disturbs cell viability and immune activation, affects β-amyloid processing, and electrophysiological analyses show that the K420Q mutation impairs the inhibitory effect of wild-type C7 on excitatory synaptic transmission in pyramidal neurons.","method":"Whole-exome sequencing, hippocampal volume MRI analysis, cell viability assays, β-amyloid processing assays, electrophysiological recordings in pyramidal neurons","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 — functional characterization of specific variant with multiple readouts including electrophysiology; single lab","pmids":["31032141"],"is_preprint":false},{"year":2012,"finding":"C7-deficient mice infected with Mycobacterium tuberculosis showed significantly reduced liver colony-forming units at day 30, markedly reduced lung occlusion, increased total lymphocytes, decreased macrophages, and increased CD4+ T cells at day 60 post-infection. Lung IFN-γ and TNF-α expression was increased in C7-deficient mice, with no differences in macrophage-level MTB proliferation. This indicates C7 contributes to MAC-mediated immunopathology in tuberculosis rather than bacterial killing.","method":"C7-knockout mouse aerosol infection model, bacterial burden (CFU), histopathology, flow cytometry, cytokine expression, macrophage proliferation assay","journal":"Clinical & developmental immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined cellular and cytokine phenotypes; single study","pmids":["22973398"],"is_preprint":false},{"year":1978,"finding":"Combined genetic deficiency of C6 and C7 was identified in a family, transmitted as a single genetic characteristic with a silent C6 allele. The propositus had an abnormal, smaller C6 (110 kDa vs normal 140 kDa) with reduced antigenicity, together with trace amounts of normal C7. The data suggest C6 and C7 genes are closely linked and may share a primary transcript, and that a structural C6 mutation can cause hyposynthesis of both C6 and C7, implying possible co-regulation.","method":"Functional complement assays, immunodiffusion, SDS-PAGE molecular weight determination, family segregation analysis","journal":"Clinical and experimental immunology","confidence":"Low","confidence_rationale":"Tier 3 — genetic/biochemical characterization of a single family; mechanism of co-regulation proposed but not directly demonstrated","pmids":["102474"],"is_preprint":false},{"year":1990,"finding":"The genes encoding human complement components C6 and C7 were both assigned to chromosome 5 by somatic cell hybrid panel analysis, with C7 detection confirmed by PCR amplification of human-specific C7 sequences in hybrid DNA.","method":"Somatic cell hybrid panel (19 hybrids), Southern blot with human C6 and C7 cDNA probes, PCR amplification of human C7 sequences","journal":"Annals of human genetics","confidence":"High","confidence_rationale":"Tier 2 — standard chromosomal assignment methodology with PCR confirmation; definitive mapping result","pmids":["2382968"],"is_preprint":false}],"current_model":"Human complement C7 is a single-chain mosaic glycoprotein (821 aa, 28 disulfide bonds) encoded on chromosome 5, synthesized primarily by liver and bone marrow (and also by monocytes, fibroblasts, and PMNs), that functions as a critical component of the membrane attack complex (MAC): upon incorporation into C5b-67, C7 undergoes a hydrophilic-to-amphiphilic transition and forms the membrane-anchoring stalk of the complex, binds plasminogen to focus plasmin activity at complement-tagged sites, and is inhibited by clusterin binding; misfolding mutations (e.g., R499S) cause ER retention and subtotal C7 deficiency, while C7 also has non-canonical roles in maintaining liver cancer stem cell properties via LSF-1 and in modulating synaptic transmission relevant to Alzheimer's disease risk."},"narrative":{"teleology":[{"year":1975,"claim":"Identification of a C7-inactivating principle in deficient serum provided early evidence that C7 activity is physiologically regulated, though the molecular identity of the regulator remained unknown.","evidence":"Functional hemolysis assays and immunodiffusion in C7-deficient human serum","pmids":["813921"],"confidence":"Low","gaps":["The molecular identity of the inactivating principle was never determined","Single study without independent replication","No mechanism of inactivation established"]},{"year":1979,"claim":"Biochemical characterization established that C6 and C7 are structurally homologous single-chain glycoproteins, supporting their origin from a common ancestral gene and implying shared mechanistic principles in MAC assembly.","evidence":"Affinity chromatography purification, amino acid composition, SDS-PAGE, CD spectroscopy of purified C6 and C7","pmids":["381516"],"confidence":"High","gaps":["No structural basis for the functional divergence of C6 and C7 despite their similarity","Sequence-level comparison not yet available"]},{"year":1988,"claim":"Determination of the complete primary structure of C7 and its role in the C5b-7 complex resolved how C7 mediates the critical hydrophilic-to-amphiphilic transition: C7 and C6 constitute the membrane-anchoring stalk of C5b-7, as demonstrated by photoreactive cross-linking and EM.","evidence":"cDNA sequencing (821 aa, 28 disulfide bonds), transmission EM, photoreactive phosphatidylethanolamine cross-linking","pmids":["3335508"],"confidence":"High","gaps":["Atomic-resolution structure of C5b-7 not determined","Precise lipid-interaction domain within C7 not mapped at residue level"]},{"year":1990,"claim":"Chromosomal mapping placed C6 and C7 genes together on chromosome 5, consistent with earlier genetic observations of co-segregation and confirming physical linkage that explains combined C6/C7 deficiencies.","evidence":"Somatic cell hybrid panel with Southern blot and PCR amplification of human C7 sequences","pmids":["2382968"],"confidence":"High","gaps":["Physical distance and shared regulatory elements between C6 and C7 loci not determined"]},{"year":1993,"claim":"Identification of clusterin as a direct binding partner of C7 (and C8β/C9) established a soluble inhibitory mechanism for MAC assembly, with clusterin recognizing conformational epitopes exposed during the amphiphilic transition.","evidence":"Radioligand binding with [125I]clusterin, competition assays, hemolysis and C9 polymerization inhibition","pmids":["8345200"],"confidence":"High","gaps":["Binding site on C7 for clusterin not mapped","Relative importance of clusterin vs. other fluid-phase MAC inhibitors in vivo unclear"]},{"year":1995,"claim":"Discovery that C7 binds plasminogen via lysine-binding sites and enhances tPA-mediated plasmin generation revealed a non-canonical role linking complement activation to fibrinolysis at complement-targeted surfaces.","evidence":"Radioligand binding with [125I]-plasminogen, lysine analogue competition, tPA-mediated plasminogen activation assay","pmids":["7814888"],"confidence":"High","gaps":["Lysine residues on C7 responsible for plasminogen binding not identified","In vivo relevance of C7-plasminogen interaction not demonstrated"]},{"year":1996,"claim":"Allotype-tracking in transplant recipients quantified organ-specific contributions to circulating C7, establishing the liver (30–62%) and bone marrow (18–27%) as the primary systemic sources, while earlier work had shown local synthesis by monocytes, fibroblasts, and PMNs.","evidence":"C7 allotype-specific ELISA in liver and bone marrow transplant recipients; serum-free monocyte/fibroblast culture; PMN allotype and PMA release experiments","pmids":["8814254","3764345","2270435","7722325"],"confidence":"Medium","gaps":["Relative contribution of extrahepatic sources under inflammatory conditions not systematically quantified","Transcriptional regulation of C7 in different cell types not characterized"]},{"year":1997,"claim":"Identification of multiple loss-of-function mutations (splice defects, exon deletions, missense) in diverse ethnic populations established the molecular genetic basis of hereditary C7 deficiency and revealed founder effects in specific populations.","evidence":"Exon PCR, direct sequencing, Southern blotting, haplotype marker analysis in Irish and Moroccan Sephardic Jewish families","pmids":["9218625"],"confidence":"Medium","gaps":["Functional consequences of the missense mutation in exon 9 not characterized at the protein level","Genotype–phenotype correlation with infection susceptibility not established"]},{"year":2007,"claim":"The R499S variant was shown to cause ER retention of misfolded C7, providing a molecular mechanism for subtotal C7 deficiency and distinguishing it from complete null mutations.","evidence":"Immunofluorescence co-localization with ER/Golgi markers in cells expressing wild-type vs. R499S C7; population frequency analysis","pmids":["17407100"],"confidence":"High","gaps":["Structural basis for R499S misfolding not determined","Whether ER-retained R499S triggers unfolded protein response not tested"]},{"year":2012,"claim":"C7-knockout mice infected with M. tuberculosis showed reduced immunopathology with altered T-cell and macrophage responses, establishing that MAC contributes to tissue damage rather than bacterial killing in tuberculosis.","evidence":"C7-KO mouse aerosol infection, CFU, histopathology, flow cytometry, cytokine profiling","pmids":["22973398"],"confidence":"Medium","gaps":["Mechanism by which MAC mediates immunopathology (direct tissue lysis vs. inflammatory amplification) not resolved","Findings not confirmed in other infection models"]},{"year":2015,"claim":"A non-canonical role for C7 in maintaining liver cancer stem cell properties was demonstrated: C7 knockdown abolished tumorsphere formation and stemness factor expression via LSF-1, while overexpression enhanced in vivo tumor growth.","evidence":"siRNA knockdown and overexpression in liver tumor-initiating cells, tumorsphere assays, xenograft models, LSF-1 pathway analysis","pmids":["26723877"],"confidence":"Medium","gaps":["Whether C7 acts intracellularly or via autocrine MAC-independent signaling is unknown","Mechanism of C7–LSF-1 regulation not elucidated","Relevance beyond hepatocellular carcinoma not tested"]},{"year":2018,"claim":"The rare C7 K420Q variant was associated with Alzheimer's disease, and functional studies showed it impairs C7's inhibitory effect on excitatory synaptic transmission, linking complement to neuronal function beyond neuroinflammation.","evidence":"Whole-exome sequencing in Han Chinese cohort, hippocampal MRI, β-amyloid processing assays, electrophysiological recordings in pyramidal neurons","pmids":["31032141"],"confidence":"Medium","gaps":["Mechanism by which wild-type C7 inhibits excitatory synaptic transmission is unknown","Whether the effect is MAC-dependent or a direct neuronal action not resolved","Single ethnic cohort — replication in other populations needed"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of C7 within the MAC and C5b-7 complexes, the precise lipid-interaction residues mediating membrane insertion, the mechanism underlying C7's non-canonical roles in cancer stemness and synaptic modulation, and whether these non-canonical functions operate through MAC-independent pathways.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of C7 alone or in the C5b-7/MAC complex","MAC-independent signaling mechanisms of C7 not delineated","Transcriptional regulation of C7 expression across tissues poorly characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,3,8,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,5,6,7,8,15]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,13,14]}],"complexes":["Membrane attack complex (MAC/C5b-9)","C5b-7 complex"],"partners":["C5","C6","C8","C9","CLU","PLG","CFH"],"other_free_text":[]},"mechanistic_narrative":"Complement component C7 is a single-chain mosaic glycoprotein that undergoes a hydrophilic-to-amphiphilic transition upon incorporation into the C5b-67 intermediate, forming the membrane-anchoring stalk of the membrane attack complex (MAC) [PMID:3335508]. Synthesized primarily by the liver and bone marrow, with additional local production by monocytes, fibroblasts, and polymorphonuclear leukocytes, C7 is also a plasminogen-binding protein that enhances tPA-mediated plasminogen activation, thereby focusing plasmin activity at complement-tagged surfaces [PMID:8814254, PMID:7814888, PMID:7722325]. Diverse loss-of-function mutations — including splice-site defects, exon deletions, and the ER-retaining missense variant R499S — cause hereditary C7 deficiency, which predisposes to Neisserial infections [PMID:9218625, PMID:17407100]. Beyond canonical MAC function, C7 has been implicated in maintaining liver cancer stem cell properties via LSF-1 regulation and in modulating excitatory synaptic transmission relevant to Alzheimer's disease [PMID:26723877, PMID:31032141]."},"prefetch_data":{"uniprot":{"accession":"P10643","full_name":"Complement component C7","aliases":[],"length_aa":843,"mass_kda":93.5,"function":"Component of the membrane attack complex (MAC), a multiprotein complex activated by the complement cascade, which inserts into a target cell membrane and forms a pore, leading to target cell membrane rupture and cell lysis (PubMed:22832194, PubMed:26841837, PubMed:27052168, PubMed:30552328, PubMed:3335508). The MAC is initiated by proteolytic cleavage of C5 into complement C5b in response to the classical, alternative, lectin and GZMK complement pathways (PubMed:22832194, PubMed:30552328, PubMed:3335508, PubMed:39914456, PubMed:39814882). The complement pathways consist in a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:22832194, PubMed:30552328, PubMed:3335508). C7 serves as a membrane anchor (PubMed:30552328). During MAC assembly, associates with C5b and C6 to form the C5b-7 complex, a key lipophilic precursor of the MAC complex, which associates with the outer leaflet and reduces the energy for membrane bending (PubMed:30552328, PubMed:32569291)","subcellular_location":"Secreted; Target cell membrane","url":"https://www.uniprot.org/uniprotkb/P10643/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C7","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/C7","total_profiled":1310},"omim":[{"mim_id":"617898","title":"MULTIPLE SYNOSTOSES SYNDROME 4; SYNS4","url":"https://www.omim.org/entry/617898"},{"mim_id":"617579","title":"CLAUDIN 10; CLDN10","url":"https://www.omim.org/entry/617579"},{"mim_id":"617457","title":"POLYMERASE III, RNA, SUBUNIT G-LIKE; POLR3GL","url":"https://www.omim.org/entry/617457"},{"mim_id":"617456","title":"POLYMERASE III, RNA, SUBUNIT G; POLR3G","url":"https://www.omim.org/entry/617456"},{"mim_id":"617063","title":"MEIER-GORLIN SYNDROME 7; MGORS7","url":"https://www.omim.org/entry/617063"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":861.4}],"url":"https://www.proteinatlas.org/search/C7"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P10643","domains":[{"cath_id":"-","chopping":"30-73","consensus_level":"medium","plddt":88.1173,"start":30,"end":73},{"cath_id":"4.10.400,4.10.400","chopping":"80-128","consensus_level":"medium","plddt":84.5978,"start":80,"end":128},{"cath_id":"2.20.100.10","chopping":"451-550","consensus_level":"medium","plddt":84.4638,"start":451,"end":550},{"cath_id":"2.10.70.10","chopping":"571-629","consensus_level":"medium","plddt":79.0014,"start":571,"end":629},{"cath_id":"2.10.70.10","chopping":"631-694","consensus_level":"medium","plddt":76.8936,"start":631,"end":694},{"cath_id":"3.30.60.30","chopping":"701-768","consensus_level":"medium","plddt":86.2122,"start":701,"end":768}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10643","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10643-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10643-F1-predicted_aligned_error_v6.png","plddt_mean":79.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C7","jax_strain_url":"https://www.jax.org/strain/search?query=C7"},"sequence":{"accession":"P10643","fasta_url":"https://rest.uniprot.org/uniprotkb/P10643.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10643/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10643"}},"corpus_meta":[{"pmid":"11881999","id":"PMC_11881999","title":"Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors.","date":"2002","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11881999","citation_count":262,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3335508","id":"PMC_3335508","title":"The structure of human complement component C7 and the C5b-7 complex.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3335508","citation_count":158,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8345200","id":"PMC_8345200","title":"Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/8345200","citation_count":140,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7559516","id":"PMC_7559516","title":"Chemical structure and translation inhibition studies of the antibiotic microcin C7.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7559516","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"6965106","id":"PMC_6965106","title":"Isolation and characterization of dexamethasone-resistant mutants from human lymphoid cell line CEM-C7.","date":"1981","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/6965106","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7679604","id":"PMC_7679604","title":"Galanin receptor antagonists M40 and C7 block galanin-induced feeding.","date":"1993","source":"Brain 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the N-terminal two-thirds and cysteine-rich segments in the C-terminal third homologous to LDL receptor, EGF precursor, thrombospondin, and coagulation factors IX/X. Electron microscopy of C5b-7 complex revealed it forms a leaflet-stalk structure where the stalk (containing C6 and C7) mediates membrane binding, establishing C7's role in the hydrophilic-amphiphilic transition and as a membrane anchor for the C5b-7 complex during MAC assembly.\",\n      \"method\": \"cDNA sequencing, circular dichroism, transmission electron microscopy, photoreactive cross-linking with radioiodinated phosphatidylethanolamine\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary structure from cDNA, structural visualization by EM, and functional cross-linking in a single rigorous study\",\n      \"pmids\": [\"3335508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Clusterin binds directly to complement C7, C8β, and the C9b fragment of C9 (which contains the hydrophobic membrane interaction segment). Binding to C9 was competed by polymerized C9 but not by C7, C6, or CD59, indicating that the conformational change during the hydrophilic-amphiphilic transition of C9 exposes the clusterin interaction site. Both subunits of clusterin inhibit C5b-9-mediated hemolysis and Zn²⁺-induced C9 polymerization by interacting with this structural motif common to C7, C8α, and C9b.\",\n      \"method\": \"Ligand blotting with [¹²⁵I]clusterin, competitive binding assays, hemolysis inhibition assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct ligand binding with competition assays and functional hemolysis readout; multiple orthogonal methods\",\n      \"pmids\": [\"8345200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"C6 and C7 share similar amino acid composition, molecular weight (~120–125 kDa), single-chain glycoprotein structure, electrophoretic mobility as β2-globulins, polymorphism by isoelectrofocusing, and similar secondary structure by CD spectroscopy, suggesting evolution from a common ancestral gene.\",\n      \"method\": \"Affinity chromatography isolation, amino acid composition analysis, isoelectrofocusing, UV and CD spectroscopy\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of purified proteins with multiple methods, single study\",\n      \"pmids\": [\"381516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"C7 is a plasminogen-binding protein. Radioligand binding studies showed that isolated C7, as well as C7 incorporated into the terminal complement complex C5b-9, binds plasminogen. Binding was inhibited by lysine analogues (6-aminohexanoic acid and tranexamic acid), implicating plasminogen lysine-binding sites. Furthermore, tissue-type plasminogen activator (tPA)-mediated plasminogen activation was enhanced in the presence of C7, identifying a functional interaction between the complement and plasminogen activator systems.\",\n      \"method\": \"Radioligand binding assay, inhibition with lysine analogues, tPA-mediated plasminogen activation assay\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay with mechanistic inhibition experiments and functional plasmin generation assay\",\n      \"pmids\": [\"7814888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"C5b6-dependent binding of ¹²⁵I-C7 to type III paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes is equal to that of normal erythrocytes, demonstrating that the enhanced reactive lysis of PNH cells is not due to increased C7 uptake. Rather, cell-bound C5b67 sites are converted to effective hemolytic sites with greater efficiency on PNH erythrocytes, and C3b deposition does not explain this, as anti-C3 antibodies did not inhibit PNH reactive lysis.\",\n      \"method\": \"¹²⁵I-C7 binding assay, hemolysis assay, antibody inhibition experiments\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct radiolabeled protein binding quantification with functional hemolysis readout; single study with multiple orthogonal approaches\",\n      \"pmids\": [\"3964820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human monocytes cultured under serum-free conditions synthesize and secrete C7 (along with C5, C6, C8, and C9), and the secreted C7 assembles into a functional terminal complement complex on the surface of agarose beads, as detected by antibody to a neoantigen of polymerized C9.\",\n      \"method\": \"Serum-free culture, immunobinding to agarose beads with anti-complement antibodies, radioimmunoassay, neoantigen detection\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional MAC assembly demonstrated with neoantigen detection; single study\",\n      \"pmids\": [\"3764345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Human fibroblasts produce C7 (and C3, C5, C6, C8, C9) in vitro, and the locally secreted C7 participates in assembly of a functional terminal complement complex, as demonstrated by detection of activated C9 neoepitope on agarose beads co-cultured with fibroblasts.\",\n      \"method\": \"Serum-free co-culture with complement activator beads, radioimmunoassay with anti-complement antibodies including neoepitope-specific anti-C9 antibody\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional complement assembly readout with neoantigen detection; single study\",\n      \"pmids\": [\"2270435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Bone marrow transplant experiments showed that donor-derived bone marrow contributes 18–27% of circulating C7, and liver transplant experiments demonstrated that the liver contributes 30–62% of circulating C7. Together these data establish the liver as the major source and bone marrow as a significant secondary source of circulating complement C7.\",\n      \"method\": \"Allotype-mismatched organ transplantation with ELISA detection of donor-specific C7 allotype using monoclonal antibody WU 4-15\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo allotype tracking in human transplant patients; definitive organ-level attribution with multiple patients\",\n      \"pmids\": [\"8814254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Polymorphonuclear leukocytes (PMNs) store large amounts of C7 and C6 intracellularly (median 149.7 ng C7 per 10⁷ PMNs), release them upon PMA stimulation in a protein-synthesis-independent manner, and the released C7 retains molecular integrity and can incorporate into the terminal complement complex, identifying PMNs as a major local source of C7 and C6 at sites of inflammation.\",\n      \"method\": \"ELISA, immunoblot, allotype tracking (incubating PMNs from C7 N donors in C7 M serum), PMA stimulation, protein synthesis inhibition\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including allotype tracking, functional incorporation assay, and stimulation experiments\",\n      \"pmids\": [\"7722325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The C7(R499S) missense mutation causes C7 deficiency by a protein-folding defect: the mutant C7(R499S) protein is retained in the endoplasmic reticulum, whereas wild-type C7 is located in the Golgi apparatus, demonstrating that R499S is a loss-of-function polymorphism due to defective protein folding and trafficking.\",\n      \"method\": \"Exon PCR and sequencing, subcellular localization by immunofluorescence/cell fractionation\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization experiment linking mutation to trafficking defect; single study\",\n      \"pmids\": [\"9218625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C7 and complement factor H (CFH) are required for maintaining stemness in liver cancer tumor-initiating cells. Knockdown of C7 and CFH abrogated tumorsphere formation and induced differentiation, while overexpression stimulated stemness factor expression and in vivo tumor growth. Mechanistically, C7 and CFH regulate stemness through LSF-1, which directly controls transcription of stemness factors.\",\n      \"method\": \"shRNA knockdown, overexpression, tumorsphere formation assay, in vivo xenograft, LSF-1 expression analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss- and gain-of-function with defined pathway placement via LSF-1; single lab study\",\n      \"pmids\": [\"26723877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A rare missense variant in C7 (p.K420Q) is functionally associated with altered cell viability, immune activation, and β-amyloid processing upon overexpression. Electrophysiological analyses showed that mutant C7(K420Q) impairs the inhibitory effect of wild-type C7 on excitatory synaptic transmission in pyramidal neurons, establishing a neuronal function for C7 in regulating synaptic transmission.\",\n      \"method\": \"Whole-exome sequencing, overexpression in cells, electrophysiology (pyramidal neuron recordings), β-amyloid processing assays\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct electrophysiology with gain-of-function; multiple functional readouts; single lab\",\n      \"pmids\": [\"31032141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In C7-deficient mice infected with Mycobacterium tuberculosis, there was markedly reduced lung occlusion, significantly increased total lymphocytes, decreased macrophages, increased CD4+ cells, and elevated IFN-γ and TNF-α expression at day 60 post-infection compared to wild-type, with no difference in MTB proliferation in isolated macrophages. This demonstrates that complement C7 contributes to lung immunopathology during tuberculosis through effects on immune cell infiltration rather than direct antimicrobial activity.\",\n      \"method\": \"C7 knockout mice, aerosol MTB challenge, histopathology, flow cytometry, cytokine measurement, macrophage MTB proliferation assay\",\n      \"journal\": \"Clinical & developmental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with defined cellular and cytokine phenotype readouts; single lab study\",\n      \"pmids\": [\"22973398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Phylogenetic analysis of the amino acid sequences of terminal complement complex components (C6, C7, C8α, C8β, C9, and perforins) establishes that C6 and C7 were the earliest to emerge from a common ancestral gene through a series of duplications, with successive components showing decreasing modular complexity.\",\n      \"method\": \"Phylogenetic analysis of protein sequences\",\n      \"journal\": \"Journal of molecular evolution\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational/phylogenetic inference only\",\n      \"pmids\": [\"10441679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The genes encoding human complement components C6 and C7 were assigned to chromosome 5 by testing a panel of somatic cell hybrids using Southern blotting with C6 and C7 cDNA probes and PCR, with detection of human C6 and C7 completely correlated with presence of chromosome 5.\",\n      \"method\": \"Somatic cell hybrid panel, Southern blotting with cDNA probes, PCR\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic mapping using established hybrid panel methodology; replicated with two independent detection methods\",\n      \"pmids\": [\"2382968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human complement C7 is a single-chain mosaic glycoprotein (821 aa, ~120 kDa) synthesized primarily by the liver and bone marrow (and locally by PMNs, monocytes, and fibroblasts) that undergoes a hydrophilic-to-amphiphilic transition upon assembly into the C5b-7 complex, where its stalk region anchors the complex to cell membranes and nucleates assembly of the membrane attack complex (C5b-9); C7 also binds plasminogen and enhances tPA-mediated plasmin generation, is inhibited by clusterin binding, and has emerging roles in synaptic transmission and liver cancer stemness via LSF-1.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI need to carefully classify each paper to determine if it's about the human complement component C7 (the canonical protein-coding gene C7, also known as complement component 7).\n\n**Classification Analysis:**\n\nThe target gene is human **C7** (complement component 7) - a serum glycoprotein involved in the membrane attack complex (MAC) of the complement system.\n\nPapers to KEEP (about complement C7):\n- [2] PMID:3335508 - Structure of human C7 and C5b-7 complex ✓\n- [3] PMID:8345200 - Clusterin binds C7, C8β, C9 ✓\n- [8] PMID:381516 - Structural similarities C6 and C7 ✓\n- [9] PMID:102474 - Combined C6/C7 deficiency ✓\n- [14] PMID:31032141 - C7 as Alzheimer's risk gene (functional characterization) ✓\n- [18] PMID:2397612 - Hereditary C7 deficiency (clinical description, some mechanism) - mostly clinical\n- [21] PMID:3764345 - Synthesis of C5-C9 by monocytes ✓\n- [25] PMID:26723877 - C7 and CFH controlling liver cancer stemness via LSF-1 ✓\n- [30] PMID:7722325 - PMNs store C7 and C6 ✓\n- [32] PMID:15088130 - Sea urchin homologues of C6/C7 ✓\n- [36] PMID:11378347 - C6 and C7 mRNA reduction in esophageal carcinoma (expression only) - EXCLUDE\n- [37] PMID:813921 - C7 deficiency with C7-inactivating principle ✓\n- [42] PMID:2270435 - C3-C9 synthesis by fibroblasts ✓\n- [45] PMID:22617254 - Grass carp C7 in innate immunity ✓\n- [51] PMID:2382968 - C6 and C7 gene assignment to chromosome 5 ✓\n- [55] PMID:3964820 - PNH erythrocytes and C7 binding ✓\n- [56] PMID:9218625 - Molecular bases of C7 deficiency ✓\n- [57] PMID:17407100 - C7 deficiency molecular defects; R499S retained in ER ✓\n- [69] PMID:8814254 - Organ-specific contribution to C7 levels (liver/bone marrow) ✓\n- [72] PMID:10072638 - Reference typing C6, C7, C9 ✓\n- [73] PMID:7625764 - DNA polymorphisms C6/C7 ✓\n- [74] PMID:10441679 - Phylogenetic analysis of TCC ✓\n- [78] PMID:7814888 - C7 is plasminogen-binding protein ✓\n- [79] PMID:7625765 - C6/C7 haplotypes in C6 deficiency ✓\n- [80] PMID:6500564 - C6/C7 polymorphism in Japanese ✓\n- [83] PMID:9856499 - C7 deficiency molecular defects ✓\n- [90] PMID:15554930 - C7 deficiency in Spanish families ✓\n- [91] PMID:1347491 - Combined C7 and C4B deficiency with SLE ✓\n- [98] PMID:29981471 - MAC components in redlip mullet ✓\n- [100] PMID:22973398 - C7 in MTB lung immunopathology ✓\n\nPapers to EXCLUDE (alias collisions, off-target):\n- [1] - C-7 position of quinazoline ring (chemistry) - EXCLUDE\n- [4] - Microcin C7 (bacterial antibiotic) - EXCLUDE\n- [5] - CEM-C7 cell line (glucocorticoid receptor) - EXCLUDE\n- [6] - C7 galanin receptor antagonist peptide - EXCLUDE\n- [7] - MDCK-C7 cell line - EXCLUDE\n- [10] - C7 steroid position hydroxylation - EXCLUDE\n- [11] - Microcin C7 biosynthesis - EXCLUDE\n- [12] - Cytochrome c7 from Geobacter (bacterial protein) - EXCLUDE\n- [13] - C7 rutinoside position (flavonoid chemistry) - EXCLUDE\n- [15] - C7 position of nucleotide (chemistry) - EXCLUDE\n- [16] - MDCK-C7 cell line - EXCLUDE\n- [17] - TrpC7 (transient receptor potential channel 7) - EXCLUDE\n- [19] - Yeast sterol C8-C7 isomerase (ERG2) - EXCLUDE\n- [20] - AcbC C7-cyclitol synthase (bacterial biosynthesis) - EXCLUDE\n- [22] - Monoclonal antibody C7 against Candida - EXCLUDE\n- [23] - C7-aryl piperlongumine (chemistry) - EXCLUDE\n- [24] - C7 largazole modification (chemistry) - EXCLUDE\n- [26] - C7 O-acetylation of sialic acids - EXCLUDE\n- [27] - OsGrx_C7 rice glutaredoxin (plant protein) - EXCLUDE\n- [28] - Clostridium papyrosolvens C7 (bacterium strain) - EXCLUDE\n- [29] - CEM-C1/C7 cell lines - EXCLUDE\n- [31] - C7 propyne analogs nucleotides (chemistry) - EXCLUDE\n- [33] - CEM-C7 cell line (glucocorticoid receptor) - EXCLUDE\n- [34] - Microcin C7 cloning - EXCLUDE\n- [35] - C7-oxygenated cholesterol (chemistry) - EXCLUDE\n- [38] - CEM-C7 cell line (glucocorticoid receptor) - EXCLUDE\n- [39] - Cytochrome c7 (bacterial protein) - EXCLUDE\n- [40] - Geobacter cytochrome c7 (bacterial protein) - EXCLUDE\n- [41] - Microcin C7 (bacterial antibiotic) - EXCLUDE\n- [43] - C7 position DMXAA derivatives (chemistry) - EXCLUDE\n- [44] - MDCK-C7 cell line - EXCLUDE\n- [46] - Lactobacillus plantarum C7 (bacterial strain) - EXCLUDE\n- [47] - C7-prenylation of tryptophan (fungal enzyme) - EXCLUDE\n- [48] - Piericidins C7/C8 (bacterial antibiotics) - EXCLUDE\n- [49] - ValC C7-cyclitol kinase (bacterial biosynthesis) - EXCLUDE\n- [50] - DXS28 (C7) DNA marker in Xp21 - EXCLUDE (this is a DNA marker, not complement C7)\n- [52] - Cytochrome c7 from Desulfuromonas (bacterial protein) - EXCLUDE\n- [53] - TYLCV C7 protein (plant virus protein) - EXCLUDE\n- [54] - C7/3-phth muscarinic receptor modulator - EXCLUDE\n- [58] - Type VII collagen C7 (COL7A1) - EXCLUDE (alias collision with COL7A1)\n- [59] - C7-modified sialic acids (chemistry) - EXCLUDE\n- [60] - Microcin C7 inactivation by MccE - EXCLUDE\n- [61] - Squalene cyclase C7 methyl position - EXCLUDE\n- [62] - Iron chelation compound C7 (EBV reactivation) - EXCLUDE\n- [63] - C7 position HIV attachment inhibitors - EXCLUDE\n- [64] - Microcin C7 degradation (bacterial protein) - EXCLUDE\n- [65] - Vaccinia virus C7 protein (poxvirus host-range protein) - EXCLUDE (symbol collision - different protein)\n- [66] - CEM-C7 cell line - EXCLUDE\n- [67] - C7 HFPO-TA (fluorinated compound) - EXCLUDE\n- [68] - Vaccinia virus C7/K1 deletion mutant - EXCLUDE\n- [70] - C7 position steroid (chemistry) - EXCLUDE\n- [71] - C6-C7 facet joint (anatomical) - EXCLUDE\n- [75] - Cytochrome c7 from Desulfuromonas (bacterial protein) - EXCLUDE\n- [76] - Sterol-C7 desaturase (ciliate) - EXCLUDE\n- [77] - Mouse C7 nucleolar protein (OXR1 homologue) - this is a different protein (mouse homologue of Drosophila L82/human OXR1), not complement C7 - EXCLUDE\n- [81] - C7 galanin antagonist - EXCLUDE\n- [82] - C5-C7 hydrocarbons (chemistry) - EXCLUDE\n- [83] PMID:9856499 - C7 deficiency molecular defects ✓ KEEP\n- [84] - BnaC7.ROT3 (Brassica napus gene, plant) - EXCLUDE\n- [85] - C7 ring system fluoroquinolones - EXCLUDE\n- [86] - C7-prenylation tryptophan (fungal enzyme) - EXCLUDE\n- [87] - C3-C7 n-alkylamines (chemistry) - EXCLUDE\n- [88] - OsGrx_C7 rice glutaredoxin (plant) - EXCLUDE\n- [89] - CpG ODN C7 (oligodeoxynucleotide adjuvant) - EXCLUDE\n- [92] PMID:21136778 - alpha-1-antitrypsin and C7 in asthma - could be complement C7 ✓\n- [93] - C7 nerve root (anatomical) - EXCLUDE\n- [94] - DXS28 (C7) DNA marker Xp21 - EXCLUDE\n- [95] - HepG2-1A2 C7 cell clone - EXCLUDE\n- [96] - CEM C-7 cell line - EXCLUDE\n- [97] - C7 terpenoid building blocks - EXCLUDE\n- [99] - C7 peptide HGF/c-Met inhibitor - EXCLUDE\n\nAdditional papers (gene2pubmed):\n- All appear to be about CXCL10/IP-10/CXCR3 system or general cDNA libraries - EXCLUDE (these are not about complement C7 - they appear to be for a different gene, likely CXCL10 which has IP-10 as alias. None are about complement C7.)\n\nNow extracting mechanistic discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"Human complement C7 is a single-chain glycoprotein of 821 amino acids with 28 disulfide bonds, organized as a mosaic protein with N-terminal homology to C8 and C9 and C-terminal cysteine-rich domains homologous to LDL receptor, EGF precursor, thrombospondin, and coagulation factors IX/X. Electron microscopy revealed a flexible elongated molecule; in the C5b-7 complex, C7 forms the stalk region that mediates hydrophilic-to-amphiphilic transition and membrane anchoring, with photoreactive cross-linking confirming that C6 and C7 constitute the membrane-anchoring stalk of the C5b-7 complex.\",\n      \"method\": \"cDNA sequencing, circular dichroism, transmission electron microscopy, photoreactive cross-linking with radioiodinated phosphatidylethanolamine\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary structure from cDNA, EM structure of complex, direct cross-linking to identify membrane-binding domain; multiple orthogonal methods in single study\",\n      \"pmids\": [\"3335508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"C6 and C7 are structurally very similar single-chain glycoproteins with nearly identical amino acid compositions, molecular weights (~120–125 kDa), electrophoretic properties (both β2-globulins), and secondary structure content, consistent with evolution from a common ancestral gene.\",\n      \"method\": \"Affinity chromatography purification, amino acid composition analysis, SDS-PAGE, isoelectric focusing, UV and CD spectroscopy\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical characterizations of purified proteins\",\n      \"pmids\": [\"381516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Clusterin (apolipoprotein J/complement inhibitor) binds specifically to complement C7, C8β, and the C9b fragment of C9 (which contains the hydrophobic membrane interaction segment). Binding to C9 is competed by polymerized C9 but not by C6, C7, or CD59, indicating that conformational changes during the hydrophilic-amphiphilic transition of C9 expose the clusterin interaction site. Both subunits of clusterin interact with C9 and equivalently inhibit C5b-9 hemolysis and zinc-induced C9 polymerization.\",\n      \"method\": \"Ligand blotting with [125I]clusterin, competition binding assays, hemolysis inhibition assays, C9 polymerization assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct radioligand binding with competition, functional hemolysis assays, multiple orthogonal approaches\",\n      \"pmids\": [\"8345200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Complement component C7 (but not C5b6, C8, or C9) is a plasminogen-binding protein. C7, both in isolated form and after incorporation into the C5b-9 terminal complement complex, binds plasminogen via lysine-binding sites (inhibited by 6-aminohexanoic acid and tranexamic acid). Tissue-type plasminogen activator (tPA)-mediated plasminogen activation is enhanced in the presence of C7, suggesting C7 focuses plasmin activity to complement-tagged structures.\",\n      \"method\": \"Radioligand binding studies with [125I]-plasminogen, competition assays with lysine analogues, tPA-mediated plasminogen activation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct radioligand binding, mechanistic competition experiments, functional plasmin activation assay\",\n      \"pmids\": [\"7814888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1975,\n      \"finding\": \"A C7-inactivating principle was identified in C7-deficient human serum that can inactivate C7 both in fluid phase and in its cell-bound state, suggesting existence of a physiological regulator of C7 activity.\",\n      \"method\": \"Functional complement hemolysis assays, immunodiffusion, physicochemical characterization of inactivator\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single study, functional assay without molecular identity of inactivator\",\n      \"pmids\": [\"813921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"In paroxysmal nocturnal hemoglobinuria (PNH) type III erythrocytes, enhanced reactive lysis by C5b-9 is not due to increased C7 binding from fluid phase; C5b6-dependent 125I-C7 binding to PNH erythrocytes is equivalent to normal erythrocytes. Instead, the increased lysis reflects more efficient conversion of cell-bound C5b67 to hemolytic sites on PNH cells, indicating a post-C7 binding defect downstream in MAC assembly. Pre-incubation with anti-C3 antibodies failed to inhibit PNH reactive lysis, ruling out cell-bound C3b as the mechanism.\",\n      \"method\": \"125I-C7 radioligand binding assays, reactive lysis hemolysis assays, anti-C3 antibody inhibition experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct quantitative radioligand binding with multiple controls establishing post-C7 mechanism; single study\",\n      \"pmids\": [\"3964820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"Human monocytes cultured under serum-free conditions synthesize and secrete complement components C5, C6, C7, C8, and C9, which assemble as a functional terminal complement complex on activator surfaces (agarose beads), as demonstrated by binding of antibodies against C5–C9 and a neoepitope of polymerized C9.\",\n      \"method\": \"Serum-free monocyte culture, immunoassay with anti-complement antibodies (including anti-polymerized C9 neoantigen), alternative pathway activation on agarose beads\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — serum-free culture eliminates serum contamination; functional MAC assembly demonstrated; single study\",\n      \"pmids\": [\"3764345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Human fibroblasts produce complement components C3, C5, C6, C7, C8, and C9 in vitro, and the locally synthesized terminal components assemble into a functional terminal complement complex on alternative pathway activator surfaces, as evidenced by anti-activated C9 neoepitope reactivity.\",\n      \"method\": \"Serum-free co-culture of fibroblasts with agarose activators, radioimmunoassay with anti-complement antibodies including anti-C9 neoepitope\",\n      \"journal\": \"Scandinavian journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — serum-free system; neoepitope detection confirms MAC assembly; single study\",\n      \"pmids\": [\"2270435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human polymorphonuclear leukocytes (PMNs) store large quantities of C7 and C6 intracellularly (median 149.7 ng and 60.1 ng per 10^7 cells respectively), independent of serum uptake, with C7 and C6 release occurring upon PMA stimulation. The stored C7 retains molecular integrity (identical MW to serum C7) and functional activity, being incorporated into the terminal complement complex.\",\n      \"method\": \"ELISA, immunoblot, allotype tracking experiment (C7 M/N allotype), PMA stimulation of PMNs, terminal complement complex functional assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allotype experiment rules out serum uptake; functional MAC incorporation demonstrated; single study\",\n      \"pmids\": [\"7722325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The majority of circulating C7 is synthesized by the liver and bone marrow. Following organ transplantation with C7 allotype mismatch, liver transplants contributed 30–62% of circulating C7, and a bone marrow transplant contributed 18–27% during post-transplant inflammation, demonstrating organ-specific origins of plasma C7.\",\n      \"method\": \"C7 allotype-specific ELISA (monoclonal antibody WU 4-15) in bone marrow and liver transplant recipients with allotype mismatch\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — natural allotype tracing in transplant patients provides direct evidence of synthesis sites; limited patient numbers\",\n      \"pmids\": [\"8814254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"C7 deficiency is caused by diverse molecular defects. In Irish families, mutations include a heterozygous 3' splice acceptor site mutation in intron 1 and a deletion of exons 7 and 8. In Israeli families of Moroccan Sephardic Jewish origin, a missense mutation in exon 9 (shared haplotype, likely ancient) causes the deficiency. These mutations result in absent or severely reduced circulating C7 protein.\",\n      \"method\": \"Exon PCR and direct sequencing, Southern blotting, haplotype marker analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct sequencing of multiple mutations; population haplotype analysis confirms founder effects; single study\",\n      \"pmids\": [\"9218625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C7 R499S missense mutation causes subtotal C7 deficiency (C7SD) by producing a misfolded protein that is retained in the endoplasmic reticulum, while wild-type C7 localizes to the Golgi apparatus. R499S represents a loss-of-function polymorphism with a frequency of ~1% in normal Caucasian populations, occurring in compound heterozygosity with complete C7 null alleles.\",\n      \"method\": \"Exon-specific PCR and sequencing, subcellular localization by immunofluorescence (ER vs. Golgi markers), population frequency analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct sequencing plus subcellular localization experiments establish mechanism of ER retention; replicated across multiple families\",\n      \"pmids\": [\"17407100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Phylogenetic analysis of terminal complement complex proteins (C6, C7, C8α, C8β, C9) demonstrates that they all originate from a single ancestral gene with complex modular composition, with C6 and C7 being the earliest diverged members. Evolution involved gene duplications and module loss, resulting in successive proteins with decreasing modular complexity; C9 and perforin represent parallel evolution toward pore-forming function.\",\n      \"method\": \"Phylogenetic analysis of amino acid sequences using all available C6–C9 and perforin sequences\",\n      \"journal\": \"Journal of molecular evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 4 — computational phylogenetic analysis only; replicated finding consistent with biochemical data from other studies\",\n      \"pmids\": [\"10441679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"C7 and complement factor H (CFH) are required to maintain stemness in liver tumor-initiating cells. Knockdown of C7 or CFH abrogates tumorsphere formation and induces differentiation, while overexpression stimulates stemness factor expression and in vivo tumor growth. Mechanistically, C7 and CFH regulate LSF-1 expression, which directly controls transcription of stemness factors.\",\n      \"method\": \"NanoString gene expression analysis of tumorspheres, siRNA knockdown, overexpression studies, tumorsphere formation assay, in vivo xenograft assay, LSF-1 interaction analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function and gain-of-function with specific cellular phenotype readout; pathway placement via LSF-1; single lab study\",\n      \"pmids\": [\"26723877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A rare missense variant p.K420Q in the C7 gene is associated with Alzheimer's disease in Han Chinese. Overexpression of mutant C7 (K420Q) disturbs cell viability and immune activation, affects β-amyloid processing, and electrophysiological analyses show that the K420Q mutation impairs the inhibitory effect of wild-type C7 on excitatory synaptic transmission in pyramidal neurons.\",\n      \"method\": \"Whole-exome sequencing, hippocampal volume MRI analysis, cell viability assays, β-amyloid processing assays, electrophysiological recordings in pyramidal neurons\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional characterization of specific variant with multiple readouts including electrophysiology; single lab\",\n      \"pmids\": [\"31032141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C7-deficient mice infected with Mycobacterium tuberculosis showed significantly reduced liver colony-forming units at day 30, markedly reduced lung occlusion, increased total lymphocytes, decreased macrophages, and increased CD4+ T cells at day 60 post-infection. Lung IFN-γ and TNF-α expression was increased in C7-deficient mice, with no differences in macrophage-level MTB proliferation. This indicates C7 contributes to MAC-mediated immunopathology in tuberculosis rather than bacterial killing.\",\n      \"method\": \"C7-knockout mouse aerosol infection model, bacterial burden (CFU), histopathology, flow cytometry, cytokine expression, macrophage proliferation assay\",\n      \"journal\": \"Clinical & developmental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular and cytokine phenotypes; single study\",\n      \"pmids\": [\"22973398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1978,\n      \"finding\": \"Combined genetic deficiency of C6 and C7 was identified in a family, transmitted as a single genetic characteristic with a silent C6 allele. The propositus had an abnormal, smaller C6 (110 kDa vs normal 140 kDa) with reduced antigenicity, together with trace amounts of normal C7. The data suggest C6 and C7 genes are closely linked and may share a primary transcript, and that a structural C6 mutation can cause hyposynthesis of both C6 and C7, implying possible co-regulation.\",\n      \"method\": \"Functional complement assays, immunodiffusion, SDS-PAGE molecular weight determination, family segregation analysis\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic/biochemical characterization of a single family; mechanism of co-regulation proposed but not directly demonstrated\",\n      \"pmids\": [\"102474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The genes encoding human complement components C6 and C7 were both assigned to chromosome 5 by somatic cell hybrid panel analysis, with C7 detection confirmed by PCR amplification of human-specific C7 sequences in hybrid DNA.\",\n      \"method\": \"Somatic cell hybrid panel (19 hybrids), Southern blot with human C6 and C7 cDNA probes, PCR amplification of human C7 sequences\",\n      \"journal\": \"Annals of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — standard chromosomal assignment methodology with PCR confirmation; definitive mapping result\",\n      \"pmids\": [\"2382968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human complement C7 is a single-chain mosaic glycoprotein (821 aa, 28 disulfide bonds) encoded on chromosome 5, synthesized primarily by liver and bone marrow (and also by monocytes, fibroblasts, and PMNs), that functions as a critical component of the membrane attack complex (MAC): upon incorporation into C5b-67, C7 undergoes a hydrophilic-to-amphiphilic transition and forms the membrane-anchoring stalk of the complex, binds plasminogen to focus plasmin activity at complement-tagged sites, and is inhibited by clusterin binding; misfolding mutations (e.g., R499S) cause ER retention and subtotal C7 deficiency, while C7 also has non-canonical roles in maintaining liver cancer stem cell properties via LSF-1 and in modulating synaptic transmission relevant to Alzheimer's disease risk.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Complement C7 is a single-chain mosaic glycoprotein (821 amino acids, ~120 kDa) that serves as an essential component of the membrane attack complex (MAC) of the terminal complement pathway, undergoing a hydrophilic-to-amphiphilic transition upon incorporation into the C5b-7 complex and anchoring it to target cell membranes via its stalk region [PMID:3335508]. C7 is produced primarily by the liver (30–62% of circulating levels) with significant secondary contributions from bone marrow (18–27%), and is also synthesized locally by polymorphonuclear leukocytes, monocytes, and fibroblasts, all of which produce functionally competent C7 capable of assembling into the terminal complement complex [PMID:8814254, PMID:7722325, PMID:3764345, PMID:2270435]. Beyond MAC assembly, C7 binds plasminogen through lysine-binding sites and enhances tPA-mediated plasmin generation, is negatively regulated by clusterin binding to its membrane-interaction domain, and modulates excitatory synaptic transmission in pyramidal neurons [PMID:7814888, PMID:8345200, PMID:31032141]. Loss-of-function mutations such as R499S cause C7 deficiency through ER retention and defective protein trafficking, and C7 deficiency in mice alters lung immunopathology during Mycobacterium tuberculosis infection by shifting immune cell infiltration and cytokine profiles [PMID:9218625, PMID:22973398].\",\n  \"teleology\": [\n    {\n      \"year\": 1979,\n      \"claim\": \"Before structural details were available, biochemical comparison of purified C6 and C7 revealed striking similarities in size, composition, and secondary structure, raising the question of whether they evolved from a common ancestor.\",\n      \"evidence\": \"Amino acid composition, isoelectrofocusing, UV and CD spectroscopy of purified human C6 and C7\",\n      \"pmids\": [\"381516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No primary sequence data to confirm structural homology\", \"No functional comparison between C6 and C7 activities\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"It was unclear whether increased complement lysis of PNH erythrocytes was due to enhanced C7 binding; radiolabeled C7 binding experiments showed equivalent C7 uptake on PNH and normal cells, establishing that PNH hypersensitivity arises from downstream efficiency of MAC pore formation rather than increased C7 deposition.\",\n      \"evidence\": \"¹²⁵I-C7 binding assay and hemolysis assay on PNH versus normal erythrocytes\",\n      \"pmids\": [\"3964820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific regulator(s) absent on PNH cells responsible for enhanced MAC efficiency were not identified in this study\"]\n    },\n    {\n      \"year\": 1986,\n      \"claim\": \"Whether extrahepatic cells could produce functionally active terminal complement components was unknown; monocytes and later fibroblasts were shown to synthesize and secrete C7 that assembles into a functional MAC, establishing local complement production at inflammatory sites.\",\n      \"evidence\": \"Serum-free culture of human monocytes (1986) and fibroblasts (1990) with radioimmunoassay and activated C9 neoepitope detection on agarose beads\",\n      \"pmids\": [\"3764345\", \"2270435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of local C7 production relative to circulating C7 at tissue sites was not determined\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"The full primary structure of C7 was unknown; cDNA sequencing revealed an 821-residue mosaic protein with domains homologous to C8/C9, LDL receptor, EGF precursor, and thrombospondin, and EM of C5b-7 showed a leaflet-stalk architecture in which the C7-containing stalk mediates membrane insertion, defining C7's structural basis for the hydrophilic-to-amphiphilic transition.\",\n      \"evidence\": \"cDNA cloning and sequencing, circular dichroism, transmission electron microscopy, photoreactive phospholipid cross-linking\",\n      \"pmids\": [\"3335508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution atomic structure of C7 and C5b-7 was not available\", \"Which specific domain undergoes the amphiphilic conformational change was not resolved\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"The chromosomal location of C7 was unknown; somatic cell hybrid mapping assigned both C6 and C7 to chromosome 5, consistent with their evolutionary relationship.\",\n      \"evidence\": \"Southern blotting and PCR with C7 cDNA probes across somatic cell hybrid panel\",\n      \"pmids\": [\"2382968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise sub-chromosomal localization and gene organization were not determined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"The mechanism by which the soluble inhibitor clusterin blocks MAC assembly was unclear; direct binding studies showed clusterin interacts with the membrane-insertion domains of C7, C8β, and C9b, establishing a shared structural motif exposed during the hydrophilic-to-amphiphilic transition as the target for clusterin-mediated complement regulation.\",\n      \"evidence\": \"¹²⁵I-clusterin ligand blotting, competitive binding assays, hemolysis and C9 polymerization inhibition assays\",\n      \"pmids\": [\"8345200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and affinity of clusterin–C7 interaction not quantified\", \"Whether clusterin acts primarily on C7 versus C9 in vivo was not resolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Two key advances resolved the cellular source and cross-pathway function of C7: PMNs were identified as a major intracellular reservoir of preformed C7 released upon stimulation, and C7 was shown to bind plasminogen and enhance tPA-mediated plasmin generation, linking complement and fibrinolysis.\",\n      \"evidence\": \"ELISA and allotype tracking of C7 from stimulated PMNs; radioligand plasminogen binding with lysine analogue inhibition and tPA activation assay\",\n      \"pmids\": [\"7722325\", \"7814888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of C7–plasminogen interaction in vivo not tested\", \"Mechanism of C7 storage in PMN granules not characterized\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"The relative organ contributions to circulating C7 were unknown; allotype-mismatched transplantation in humans established the liver as the dominant source (30–62%) with bone marrow contributing 18–27%, providing definitive in vivo quantitation.\",\n      \"evidence\": \"Allotype-specific ELISA in liver and bone marrow transplant recipients\",\n      \"pmids\": [\"8814254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of other organs (e.g. adipose, intestine) was not assessed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"How specific mutations cause C7 deficiency was unknown; the R499S missense mutation was shown to cause ER retention of misfolded C7, establishing defective protein trafficking as a molecular mechanism of C7 deficiency.\",\n      \"evidence\": \"Exon sequencing, immunofluorescence, and cell fractionation comparing wild-type and R499S C7\",\n      \"pmids\": [\"9218625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether other C7 deficiency alleles share the same ER retention mechanism was not tested\", \"Structural basis of R499S misfolding not determined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether C7/MAC contributes to infectious disease immunopathology beyond direct lysis was unknown; C7-knockout mice infected with M. tuberculosis showed reduced lung pathology with altered lymphocyte and macrophage infiltration and elevated IFN-γ/TNF-α, demonstrating C7 promotes immunopathology through modulation of immune cell recruitment rather than direct bacterial killing.\",\n      \"evidence\": \"C7 knockout mice, aerosol MTB infection, histopathology, flow cytometry, cytokine measurement\",\n      \"pmids\": [\"22973398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAC pore formation or sub-lytic MAC signaling mediates the immunopathology was not resolved\", \"Mechanism of C7-dependent immune cell recruitment not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"C7 was found to have an unexpected role in liver cancer stemness: knockdown abrogated tumorsphere formation while overexpression promoted tumor growth in vivo, with the effect mediated through LSF-1-dependent transcription of stemness factors.\",\n      \"evidence\": \"shRNA knockdown, overexpression, tumorsphere assays, xenograft models, LSF-1 expression analysis in liver cancer cells\",\n      \"pmids\": [\"26723877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the stemness function requires complement activation or is MAC-independent is unknown\", \"Single lab finding; independent replication lacking\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Beyond immunity, C7 was shown to have a neuronal function: wild-type C7 inhibits excitatory synaptic transmission in pyramidal neurons, and the K420Q variant impairs this inhibitory effect, establishing C7 as a regulator of synaptic activity.\",\n      \"evidence\": \"Whole-exome sequencing, electrophysiology in pyramidal neurons, overexpression of WT and K420Q C7\",\n      \"pmids\": [\"31032141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor or mechanism by which C7 modulates synaptic transmission is unknown\", \"Whether neuronal C7 function is complement-dependent or independent is unresolved\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"High-resolution structural determination of C7 alone and within the C5b-7/MAC complex, the molecular basis of C7's non-complement functions in synaptic regulation and cancer stemness, and the in vivo significance of C7–plasminogen interactions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of human C7 or C5b-7 from the timeline\", \"Mechanism of C7's synaptic and stemness functions not defined\", \"In vivo relevance of C7–plasminogen binding untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 6, 7, 8]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 6, 7, 8, 12]}\n    ],\n    \"complexes\": [\n      \"C5b-7\",\n      \"C5b-9 (MAC)\"\n    ],\n    \"partners\": [\n      \"C6\",\n      \"C5b\",\n      \"C8\",\n      \"C9\",\n      \"CLU\",\n      \"PLG\",\n      \"CFH\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Complement component C7 is a single-chain mosaic glycoprotein that undergoes a hydrophilic-to-amphiphilic transition upon incorporation into the C5b-67 intermediate, forming the membrane-anchoring stalk of the membrane attack complex (MAC) [PMID:3335508]. Synthesized primarily by the liver and bone marrow, with additional local production by monocytes, fibroblasts, and polymorphonuclear leukocytes, C7 is also a plasminogen-binding protein that enhances tPA-mediated plasminogen activation, thereby focusing plasmin activity at complement-tagged surfaces [PMID:8814254, PMID:7814888, PMID:7722325]. Diverse loss-of-function mutations — including splice-site defects, exon deletions, and the ER-retaining missense variant R499S — cause hereditary C7 deficiency, which predisposes to Neisserial infections [PMID:9218625, PMID:17407100]. Beyond canonical MAC function, C7 has been implicated in maintaining liver cancer stem cell properties via LSF-1 regulation and in modulating excitatory synaptic transmission relevant to Alzheimer's disease [PMID:26723877, PMID:31032141].\",\n  \"teleology\": [\n    {\n      \"year\": 1975,\n      \"claim\": \"Identification of a C7-inactivating principle in deficient serum provided early evidence that C7 activity is physiologically regulated, though the molecular identity of the regulator remained unknown.\",\n      \"evidence\": \"Functional hemolysis assays and immunodiffusion in C7-deficient human serum\",\n      \"pmids\": [\"813921\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"The molecular identity of the inactivating principle was never determined\", \"Single study without independent replication\", \"No mechanism of inactivation established\"]\n    },\n    {\n      \"year\": 1979,\n      \"claim\": \"Biochemical characterization established that C6 and C7 are structurally homologous single-chain glycoproteins, supporting their origin from a common ancestral gene and implying shared mechanistic principles in MAC assembly.\",\n      \"evidence\": \"Affinity chromatography purification, amino acid composition, SDS-PAGE, CD spectroscopy of purified C6 and C7\",\n      \"pmids\": [\"381516\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for the functional divergence of C6 and C7 despite their similarity\", \"Sequence-level comparison not yet available\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Determination of the complete primary structure of C7 and its role in the C5b-7 complex resolved how C7 mediates the critical hydrophilic-to-amphiphilic transition: C7 and C6 constitute the membrane-anchoring stalk of C5b-7, as demonstrated by photoreactive cross-linking and EM.\",\n      \"evidence\": \"cDNA sequencing (821 aa, 28 disulfide bonds), transmission EM, photoreactive phosphatidylethanolamine cross-linking\",\n      \"pmids\": [\"3335508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of C5b-7 not determined\", \"Precise lipid-interaction domain within C7 not mapped at residue level\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Chromosomal mapping placed C6 and C7 genes together on chromosome 5, consistent with earlier genetic observations of co-segregation and confirming physical linkage that explains combined C6/C7 deficiencies.\",\n      \"evidence\": \"Somatic cell hybrid panel with Southern blot and PCR amplification of human C7 sequences\",\n      \"pmids\": [\"2382968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical distance and shared regulatory elements between C6 and C7 loci not determined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of clusterin as a direct binding partner of C7 (and C8β/C9) established a soluble inhibitory mechanism for MAC assembly, with clusterin recognizing conformational epitopes exposed during the amphiphilic transition.\",\n      \"evidence\": \"Radioligand binding with [125I]clusterin, competition assays, hemolysis and C9 polymerization inhibition\",\n      \"pmids\": [\"8345200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site on C7 for clusterin not mapped\", \"Relative importance of clusterin vs. other fluid-phase MAC inhibitors in vivo unclear\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery that C7 binds plasminogen via lysine-binding sites and enhances tPA-mediated plasmin generation revealed a non-canonical role linking complement activation to fibrinolysis at complement-targeted surfaces.\",\n      \"evidence\": \"Radioligand binding with [125I]-plasminogen, lysine analogue competition, tPA-mediated plasminogen activation assay\",\n      \"pmids\": [\"7814888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lysine residues on C7 responsible for plasminogen binding not identified\", \"In vivo relevance of C7-plasminogen interaction not demonstrated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Allotype-tracking in transplant recipients quantified organ-specific contributions to circulating C7, establishing the liver (30–62%) and bone marrow (18–27%) as the primary systemic sources, while earlier work had shown local synthesis by monocytes, fibroblasts, and PMNs.\",\n      \"evidence\": \"C7 allotype-specific ELISA in liver and bone marrow transplant recipients; serum-free monocyte/fibroblast culture; PMN allotype and PMA release experiments\",\n      \"pmids\": [\"8814254\", \"3764345\", \"2270435\", \"7722325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of extrahepatic sources under inflammatory conditions not systematically quantified\", \"Transcriptional regulation of C7 in different cell types not characterized\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of multiple loss-of-function mutations (splice defects, exon deletions, missense) in diverse ethnic populations established the molecular genetic basis of hereditary C7 deficiency and revealed founder effects in specific populations.\",\n      \"evidence\": \"Exon PCR, direct sequencing, Southern blotting, haplotype marker analysis in Irish and Moroccan Sephardic Jewish families\",\n      \"pmids\": [\"9218625\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of the missense mutation in exon 9 not characterized at the protein level\", \"Genotype–phenotype correlation with infection susceptibility not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The R499S variant was shown to cause ER retention of misfolded C7, providing a molecular mechanism for subtotal C7 deficiency and distinguishing it from complete null mutations.\",\n      \"evidence\": \"Immunofluorescence co-localization with ER/Golgi markers in cells expressing wild-type vs. R499S C7; population frequency analysis\",\n      \"pmids\": [\"17407100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for R499S misfolding not determined\", \"Whether ER-retained R499S triggers unfolded protein response not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"C7-knockout mice infected with M. tuberculosis showed reduced immunopathology with altered T-cell and macrophage responses, establishing that MAC contributes to tissue damage rather than bacterial killing in tuberculosis.\",\n      \"evidence\": \"C7-KO mouse aerosol infection, CFU, histopathology, flow cytometry, cytokine profiling\",\n      \"pmids\": [\"22973398\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which MAC mediates immunopathology (direct tissue lysis vs. inflammatory amplification) not resolved\", \"Findings not confirmed in other infection models\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A non-canonical role for C7 in maintaining liver cancer stem cell properties was demonstrated: C7 knockdown abolished tumorsphere formation and stemness factor expression via LSF-1, while overexpression enhanced in vivo tumor growth.\",\n      \"evidence\": \"siRNA knockdown and overexpression in liver tumor-initiating cells, tumorsphere assays, xenograft models, LSF-1 pathway analysis\",\n      \"pmids\": [\"26723877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether C7 acts intracellularly or via autocrine MAC-independent signaling is unknown\", \"Mechanism of C7–LSF-1 regulation not elucidated\", \"Relevance beyond hepatocellular carcinoma not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The rare C7 K420Q variant was associated with Alzheimer's disease, and functional studies showed it impairs C7's inhibitory effect on excitatory synaptic transmission, linking complement to neuronal function beyond neuroinflammation.\",\n      \"evidence\": \"Whole-exome sequencing in Han Chinese cohort, hippocampal MRI, β-amyloid processing assays, electrophysiological recordings in pyramidal neurons\",\n      \"pmids\": [\"31032141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which wild-type C7 inhibits excitatory synaptic transmission is unknown\", \"Whether the effect is MAC-dependent or a direct neuronal action not resolved\", \"Single ethnic cohort — replication in other populations needed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of C7 within the MAC and C5b-7 complexes, the precise lipid-interaction residues mediating membrane insertion, the mechanism underlying C7's non-canonical roles in cancer stemness and synaptic modulation, and whether these non-canonical functions operate through MAC-independent pathways.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of C7 alone or in the C5b-7/MAC complex\", \"MAC-independent signaling mechanisms of C7 not delineated\", \"Transcriptional regulation of C7 expression across tissues poorly characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 3, 8, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6, 7, 8, 15]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 13, 14]}\n    ],\n    \"complexes\": [\n      \"Membrane attack complex (MAC/C5b-9)\",\n      \"C5b-7 complex\"\n    ],\n    \"partners\": [\n      \"C5\",\n      \"C6\",\n      \"C8\",\n      \"C9\",\n      \"CLU\",\n      \"PLG\",\n      \"CFH\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}