{"gene":"CFI","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1973,"finding":"Complement factor I (CFI/KAF, C3b inactivator) controls the alternative complement pathway by inactivating C3b; immunochemical depletion of KAF from serum leads to spontaneous alternative pathway activation with conversion of C3, demonstrating that the alternative pathway is essentially a C3b-feedback pathway normally controlled by CFI activity.","method":"Immunochemical depletion of KAF using purified F(ab′)2 antibody, in vitro complement activation assays","journal":"Immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution/depletion experiment with clear mechanistic readout, foundational paper replicated by subsequent work","pmids":["4632688"],"is_preprint":false},{"year":2007,"finding":"CFI is a two-chain serine protease whose light chain carries the catalytic domain; it downregulates complement by cleaving the alpha′ chains of C3b and C4b in the presence of cofactor proteins. Disease-associated mutations in the serine protease domain (I322T, D501N, D506V) abolish C3b and C4b cofactor activity, while a heavy-chain mutation (R299W) also reduces cofactor activity, indicating the heavy chain participates in cofactor-dependent cleavage.","method":"Recombinant mutant protein expression, functional cofactor activity assays measuring C3b and C4b cleavage","journal":"Molecular immunology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzyme assay with defined mutations, multiple mutants tested with clear mechanistic interpretation","pmids":["17597211"],"is_preprint":false},{"year":2013,"finding":"A rare missense CFI variant (p.Gly119Arg) reduces both expression/secretion of FI protein and its activity in degrading C3b (both in fluid phase and on cell surface); reduced CFI mRNA/protein activity was further validated by a zebrafish retinal vascularization assay showing impaired complement regulation.","method":"Recombinant protein expression and secretion assays, C3b degradation functional assays in plasma/sera, zebrafish in vivo retinal vascular assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including recombinant protein, functional serum assay, and in vivo model","pmids":["23685748"],"is_preprint":false},{"year":2013,"finding":"The C3 variant encoding Gln155 (p.Lys155Gln) is resistant to proteolytic inactivation by CFH and CFI, demonstrating that CFI-mediated cleavage of C3b is sequence-dependent and that this variant escapes regulation, leading to excessive alternative complement activation.","method":"Functional proteolytic inactivation assay using recombinant/purified proteins with CFH and CFI","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution assay showing substrate resistance to CFI cleavage","pmids":["24036952"],"is_preprint":false},{"year":2015,"finding":"Rare genetic variants in CFI commonly result in reduced circulating serum Factor I (FI) protein levels; individuals with low FI levels have markedly increased risk of advanced AMD, establishing that quantitative FI deficiency (not merely genetic variant carrier status) is the mechanistic driver of complement dysregulation in AMD.","method":"Serum FI ELISA measurement in variant carriers and non-carriers, statistical association of FI levels with AMD risk","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein quantification linking CFI variants to FI level reduction; single study but large cohort with functional readout","pmids":["25788521"],"is_preprint":false},{"year":2017,"finding":"Systematic functional testing of 20 rare CFI coding variants in a zebrafish retinal vascularization assay identified nine variants that alter CFI function, six of which are hypoactive (loss of complement regulatory activity), demonstrating that multiple rare alleles contribute to AMD through reduced FI activity.","method":"Targeted sequencing of CFI, zebrafish in vivo retinal vascular assay as surrogate for CFI function","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 — systematic in vivo functional screen across multiple variants; single lab but consistent with complementary serum-based data","pmids":["28282489"],"is_preprint":false},{"year":2017,"finding":"Complete CFI deficiency caused by homozygous mutations (p.Gly162Asp and p.His380Arg) abolishes FI protein function; p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, Ser525), directly confirming the serine protease catalytic mechanism of CFI.","method":"Genetic sequencing of CFI, complement functional testing confirming absent FI activity","journal":"Journal of clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — identification of catalytic triad residue mutation with demonstrated functional abolition; single study, clinical case series","pmids":["28942469"],"is_preprint":false},{"year":2020,"finding":"A serum-based functional assay stratified rare CFI variants into three mechanistic types: Type 1 (low FI antigen and low function), Type 2 (normal antigen but reduced C3b-to-iC3b cleavage in Factor H-dependent assay), and Type 3 (normal antigen and cleavage but reduced activity per unit FI), comprehensively mapping the mechanistic spectrum of CFI variant dysfunction.","method":"Sandwich ELISA for FI antigen levels, functional C3b proteolytic cleavage assay using Factor H as cofactor in patient sera","journal":"Translational vision science & technology","confidence":"Medium","confidence_rationale":"Tier 2 — systematic functional classification using orthogonal antigen and activity assays in a large patient cohort","pmids":["32908800"],"is_preprint":false},{"year":2008,"finding":"The molecular basis of CFI polymorphism was established: the CFI*A allele is divided into two suballeles (R201S and R406H substitutions), defining the population genetics and protein sequence variation underlying CFI isoelectric focusing polymorphism.","method":"Sequencing of CFI in 2,471 individuals across 20 populations, correlation with isoelectric focusing patterns","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 — characterizes protein polymorphism at sequence level but does not test functional consequence of variants","pmids":["18825487"],"is_preprint":false}],"current_model":"CFI encodes complement factor I, a two-chain serine protease (catalytic triad: His380, Asp429, Ser525 in the light chain) that is the principal negative regulator of the complement system; it cleaves the alpha′ chains of C3b and C4b in a reaction absolutely dependent on cofactor proteins (Factor H for the alternative pathway, C4BP/CR1 for the classical pathway), thereby converting C3b to iC3b and preventing uncontrolled alternative and classical complement activation; loss-of-function mutations reduce FI secretion, abolish cofactor-dependent proteolytic activity, or impair catalytic triad function, leading to uncontrolled C3 consumption, and are causally linked to atypical HUS and advanced age-related macular degeneration."},"narrative":{"teleology":[{"year":1973,"claim":"Resolving whether the alternative complement pathway is constitutively active or triggered: immunochemical removal of CFI from serum demonstrated that the alternative pathway functions as a C3b-positive-feedback loop normally held in check by CFI-mediated C3b inactivation.","evidence":"Immunochemical depletion of KAF (CFI) from human serum followed by complement activation assays","pmids":["4632688"],"confidence":"High","gaps":["Cofactor requirement for CFI cleavage not yet identified","Molecular identity and chain structure of CFI not determined","Mechanism by which CFI recognizes C3b versus native C3 unknown"]},{"year":2007,"claim":"Establishing the domain-level mechanism of CFI catalysis: recombinant mutant analysis showed that the light-chain serine protease domain performs cofactor-dependent cleavage of C3b and C4b, while the heavy chain contributes to substrate/cofactor recognition, as mutations in both chains abolish activity.","evidence":"Recombinant expression of CFI mutants (I322T, D501N, D506V in light chain; R299W in heavy chain) with functional C3b/C4b cofactor activity assays","pmids":["17597211"],"confidence":"High","gaps":["Structural basis for heavy-chain contribution to cofactor-dependent cleavage not resolved","Specific cofactor binding sites on CFI not mapped","No crystal structure of CFI–cofactor–substrate complex available"]},{"year":2013,"claim":"Linking CFI variant dysfunction to disease and substrate specificity: the p.Gly119Arg CFI variant was shown to reduce both secretion and C3b-degrading activity, connecting quantitative and qualitative FI deficiency to complement dysregulation; independently, a C3 substrate variant (p.Lys155Gln) was shown to resist CFI/CFH-mediated cleavage, establishing that CFI activity is substrate-sequence-dependent.","evidence":"Recombinant protein secretion assays, C3b degradation in plasma, zebrafish retinal vascular assay (for CFI variant); reconstituted proteolytic inactivation assay with purified proteins (for C3 variant)","pmids":["23685748","24036952"],"confidence":"High","gaps":["Structural determinants on C3b recognized by CFI during cleavage not defined","Whether substrate sequence variants affect all cofactor-dependent pathways equally is untested"]},{"year":2015,"claim":"Demonstrating that reduced circulating FI protein level—not merely genetic variant carrier status—is the proximate risk factor for AMD, establishing quantitative FI deficiency as the mechanistic driver.","evidence":"Serum FI ELISA in large cohort of rare CFI variant carriers and non-carriers, statistical association with advanced AMD risk","pmids":["25788521"],"confidence":"Medium","gaps":["Threshold FI level below which complement dysregulation occurs not defined","Whether FI supplementation can rescue AMD phenotype untested","Tissue-specific (retinal) FI expression and its contribution not separated from circulating pool"]},{"year":2017,"claim":"Identifying the catalytic triad and systematically classifying variant effects: a homozygous His380Arg mutation directly confirmed His380 as part of the catalytic triad (His380/Asp429/Ser525), and systematic in vivo testing of 20 rare CFI variants stratified alleles by functional consequence, revealing that multiple rare hypoactive alleles contribute to AMD.","evidence":"Genetic sequencing and complement functional testing of catalytic triad mutant; zebrafish retinal vascularization assay screening 20 CFI variants","pmids":["28942469","28282489"],"confidence":"Medium","gaps":["Only one catalytic triad residue mutation characterized; Asp429 and Ser525 mutations not yet reported in patients","Zebrafish assay is a surrogate; direct correspondence to human retinal complement regulation assumed but not proven"]},{"year":2020,"claim":"Establishing a mechanistic classification of CFI variant dysfunction: serum-based assays stratified rare variants into Type 1 (low antigen/low function), Type 2 (normal antigen/reduced cleavage), and Type 3 (normal antigen and cleavage/reduced specific activity), providing a comprehensive framework for genotype–mechanism correlation.","evidence":"Sandwich ELISA for FI antigen combined with Factor H-dependent C3b proteolytic cleavage assay in patient sera","pmids":["32908800"],"confidence":"Medium","gaps":["Structural basis distinguishing Type 2 from Type 3 dysfunction not determined","Whether this classification predicts clinical severity or therapeutic response is untested","Assay uses only Factor H as cofactor; behavior with CR1 or C4BP cofactors not assessed"]},{"year":null,"claim":"No high-resolution structure of the CFI–cofactor–C3b ternary complex exists, and the molecular basis for how cofactor binding activates CFI catalysis and directs substrate cleavage site specificity remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of CFI in complex with cofactor and substrate","Allosteric mechanism by which cofactor binding activates the CFI serine protease domain unknown","Whether therapeutic FI supplementation can restore complement regulation in vivo not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,3,6,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,4,7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3,7]}],"complexes":[],"partners":["CFH","C3B","C4B"],"other_free_text":[]},"mechanistic_narrative":"Complement factor I (CFI) is the principal serine protease responsible for negative regulation of the complement system, controlling both the alternative and classical pathways by cleaving the α′ chains of C3b and C4b in a cofactor-dependent manner. CFI functions as a two-chain protease whose light chain harbors the catalytic triad (His380, Asp429, Ser525) and whose heavy chain also participates in cofactor-dependent substrate recognition; cofactor proteins such as Factor H, C4BP, and CR1 are absolutely required for proteolytic activity, converting C3b to iC3b and preventing uncontrolled C3 consumption [PMID:4632688, PMID:17597211, PMID:28942469]. Disease-associated CFI mutations cause loss of function through three distinct mechanisms—reduced protein secretion/antigen levels, impaired catalytic activity with normal secretion, or reduced specific activity per molecule—and these deficiencies are causally linked to atypical hemolytic uremic syndrome and advanced age-related macular degeneration [PMID:25788521, PMID:32908800, PMID:23685748]. Immunochemical depletion of CFI from serum triggers spontaneous alternative pathway activation, establishing that the alternative pathway operates as a constitutive C3b-feedback loop held in check by CFI [PMID:4632688]."},"prefetch_data":{"uniprot":{"accession":"P05156","full_name":"Complement factor I","aliases":["C3B/C4B inactivator"],"length_aa":583,"mass_kda":65.8,"function":"Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways. Inhibits these pathways by cleaving three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins (PubMed:17320177, PubMed:7360115). Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces (PubMed:12055245, PubMed:2141838, PubMed:9605165). The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization (PubMed:28671664)","subcellular_location":"Secreted, extracellular space; Secreted","url":"https://www.uniprot.org/uniprotkb/P05156/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFI","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/CFI","total_profiled":1310},"omim":[{"mim_id":"615591","title":"MACULAR DEGENERATION, AGE-RELATED, 15; ARMD15","url":"https://www.omim.org/entry/615591"},{"mim_id":"615439","title":"MACULAR DEGENERATION, AGE-RELATED, 13; ARMD13","url":"https://www.omim.org/entry/615439"},{"mim_id":"614809","title":"C3 GLOMERULOPATHY 3; C3G3","url":"https://www.omim.org/entry/614809"},{"mim_id":"612925","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5; AHUS5","url":"https://www.omim.org/entry/612925"},{"mim_id":"612923","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3; AHUS3","url":"https://www.omim.org/entry/612923"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":917.6}],"url":"https://www.proteinatlas.org/search/CFI"},"hgnc":{"alias_symbol":["FI","C3b-INA","C3bINA","KAF"],"prev_symbol":["IF"]},"alphafold":{"accession":"P05156","domains":[{"cath_id":"3.10.250.10","chopping":"109-322","consensus_level":"medium","plddt":87.3659,"start":109,"end":322},{"cath_id":"2.40.10.10","chopping":"325-332_342-583","consensus_level":"medium","plddt":86.1738,"start":325,"end":583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P05156","model_url":"https://alphafold.ebi.ac.uk/files/AF-P05156-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P05156-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFI","jax_strain_url":"https://www.jax.org/strain/search?query=CFI"},"sequence":{"accession":"P05156","fasta_url":"https://rest.uniprot.org/uniprotkb/P05156.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P05156/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P05156"}},"corpus_meta":[{"pmid":"24036952","id":"PMC_24036952","title":"Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24036952","citation_count":292,"is_preprint":false},{"pmid":"16642048","id":"PMC_16642048","title":"Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).","date":"2006","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/16642048","citation_count":172,"is_preprint":false},{"pmid":"23685748","id":"PMC_23685748","title":"A functional variant in the CFI gene confers a high risk of age-related macular degeneration.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23685748","citation_count":162,"is_preprint":false},{"pmid":"4632688","id":"PMC_4632688","title":"The alternate pathway of complement activation. 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antibody, in vitro complement activation assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution/depletion experiment with clear mechanistic readout, foundational paper replicated by subsequent work\",\n      \"pmids\": [\"4632688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CFI is a two-chain serine protease whose light chain carries the catalytic domain; it downregulates complement by cleaving the alpha′ chains of C3b and C4b in the presence of cofactor proteins. Disease-associated mutations in the serine protease domain (I322T, D501N, D506V) abolish C3b and C4b cofactor activity, while a heavy-chain mutation (R299W) also reduces cofactor activity, indicating the heavy chain participates in cofactor-dependent cleavage.\",\n      \"method\": \"Recombinant mutant protein expression, functional cofactor activity assays measuring C3b and C4b cleavage\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzyme assay with defined mutations, multiple mutants tested with clear mechanistic interpretation\",\n      \"pmids\": [\"17597211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A rare missense CFI variant (p.Gly119Arg) reduces both expression/secretion of FI protein and its activity in degrading C3b (both in fluid phase and on cell surface); reduced CFI mRNA/protein activity was further validated by a zebrafish retinal vascularization assay showing impaired complement regulation.\",\n      \"method\": \"Recombinant protein expression and secretion assays, C3b degradation functional assays in plasma/sera, zebrafish in vivo retinal vascular assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including recombinant protein, functional serum assay, and in vivo model\",\n      \"pmids\": [\"23685748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The C3 variant encoding Gln155 (p.Lys155Gln) is resistant to proteolytic inactivation by CFH and CFI, demonstrating that CFI-mediated cleavage of C3b is sequence-dependent and that this variant escapes regulation, leading to excessive alternative complement activation.\",\n      \"method\": \"Functional proteolytic inactivation assay using recombinant/purified proteins with CFH and CFI\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution assay showing substrate resistance to CFI cleavage\",\n      \"pmids\": [\"24036952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Rare genetic variants in CFI commonly result in reduced circulating serum Factor I (FI) protein levels; individuals with low FI levels have markedly increased risk of advanced AMD, establishing that quantitative FI deficiency (not merely genetic variant carrier status) is the mechanistic driver of complement dysregulation in AMD.\",\n      \"method\": \"Serum FI ELISA measurement in variant carriers and non-carriers, statistical association of FI levels with AMD risk\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein quantification linking CFI variants to FI level reduction; single study but large cohort with functional readout\",\n      \"pmids\": [\"25788521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Systematic functional testing of 20 rare CFI coding variants in a zebrafish retinal vascularization assay identified nine variants that alter CFI function, six of which are hypoactive (loss of complement regulatory activity), demonstrating that multiple rare alleles contribute to AMD through reduced FI activity.\",\n      \"method\": \"Targeted sequencing of CFI, zebrafish in vivo retinal vascular assay as surrogate for CFI function\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic in vivo functional screen across multiple variants; single lab but consistent with complementary serum-based data\",\n      \"pmids\": [\"28282489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Complete CFI deficiency caused by homozygous mutations (p.Gly162Asp and p.His380Arg) abolishes FI protein function; p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, Ser525), directly confirming the serine protease catalytic mechanism of CFI.\",\n      \"method\": \"Genetic sequencing of CFI, complement functional testing confirming absent FI activity\",\n      \"journal\": \"Journal of clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identification of catalytic triad residue mutation with demonstrated functional abolition; single study, clinical case series\",\n      \"pmids\": [\"28942469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A serum-based functional assay stratified rare CFI variants into three mechanistic types: Type 1 (low FI antigen and low function), Type 2 (normal antigen but reduced C3b-to-iC3b cleavage in Factor H-dependent assay), and Type 3 (normal antigen and cleavage but reduced activity per unit FI), comprehensively mapping the mechanistic spectrum of CFI variant dysfunction.\",\n      \"method\": \"Sandwich ELISA for FI antigen levels, functional C3b proteolytic cleavage assay using Factor H as cofactor in patient sera\",\n      \"journal\": \"Translational vision science & technology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic functional classification using orthogonal antigen and activity assays in a large patient cohort\",\n      \"pmids\": [\"32908800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The molecular basis of CFI polymorphism was established: the CFI*A allele is divided into two suballeles (R201S and R406H substitutions), defining the population genetics and protein sequence variation underlying CFI isoelectric focusing polymorphism.\",\n      \"method\": \"Sequencing of CFI in 2,471 individuals across 20 populations, correlation with isoelectric focusing patterns\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — characterizes protein polymorphism at sequence level but does not test functional consequence of variants\",\n      \"pmids\": [\"18825487\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFI encodes complement factor I, a two-chain serine protease (catalytic triad: His380, Asp429, Ser525 in the light chain) that is the principal negative regulator of the complement system; it cleaves the alpha′ chains of C3b and C4b in a reaction absolutely dependent on cofactor proteins (Factor H for the alternative pathway, C4BP/CR1 for the classical pathway), thereby converting C3b to iC3b and preventing uncontrolled alternative and classical complement activation; loss-of-function mutations reduce FI secretion, abolish cofactor-dependent proteolytic activity, or impair catalytic triad function, leading to uncontrolled C3 consumption, and are causally linked to atypical HUS and advanced age-related macular degeneration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Complement factor I (CFI) is the principal serine protease responsible for negative regulation of the complement system, controlling both the alternative and classical pathways by cleaving the α′ chains of C3b and C4b in a cofactor-dependent manner. CFI functions as a two-chain protease whose light chain harbors the catalytic triad (His380, Asp429, Ser525) and whose heavy chain also participates in cofactor-dependent substrate recognition; cofactor proteins such as Factor H, C4BP, and CR1 are absolutely required for proteolytic activity, converting C3b to iC3b and preventing uncontrolled C3 consumption [PMID:4632688, PMID:17597211, PMID:28942469]. Disease-associated CFI mutations cause loss of function through three distinct mechanisms—reduced protein secretion/antigen levels, impaired catalytic activity with normal secretion, or reduced specific activity per molecule—and these deficiencies are causally linked to atypical hemolytic uremic syndrome and advanced age-related macular degeneration [PMID:25788521, PMID:32908800, PMID:23685748]. Immunochemical depletion of CFI from serum triggers spontaneous alternative pathway activation, establishing that the alternative pathway operates as a constitutive C3b-feedback loop held in check by CFI [PMID:4632688].\",\n  \"teleology\": [\n    {\n      \"year\": 1973,\n      \"claim\": \"Resolving whether the alternative complement pathway is constitutively active or triggered: immunochemical removal of CFI from serum demonstrated that the alternative pathway functions as a C3b-positive-feedback loop normally held in check by CFI-mediated C3b inactivation.\",\n      \"evidence\": \"Immunochemical depletion of KAF (CFI) from human serum followed by complement activation assays\",\n      \"pmids\": [\"4632688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cofactor requirement for CFI cleavage not yet identified\",\n        \"Molecular identity and chain structure of CFI not determined\",\n        \"Mechanism by which CFI recognizes C3b versus native C3 unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing the domain-level mechanism of CFI catalysis: recombinant mutant analysis showed that the light-chain serine protease domain performs cofactor-dependent cleavage of C3b and C4b, while the heavy chain contributes to substrate/cofactor recognition, as mutations in both chains abolish activity.\",\n      \"evidence\": \"Recombinant expression of CFI mutants (I322T, D501N, D506V in light chain; R299W in heavy chain) with functional C3b/C4b cofactor activity assays\",\n      \"pmids\": [\"17597211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for heavy-chain contribution to cofactor-dependent cleavage not resolved\",\n        \"Specific cofactor binding sites on CFI not mapped\",\n        \"No crystal structure of CFI–cofactor–substrate complex available\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking CFI variant dysfunction to disease and substrate specificity: the p.Gly119Arg CFI variant was shown to reduce both secretion and C3b-degrading activity, connecting quantitative and qualitative FI deficiency to complement dysregulation; independently, a C3 substrate variant (p.Lys155Gln) was shown to resist CFI/CFH-mediated cleavage, establishing that CFI activity is substrate-sequence-dependent.\",\n      \"evidence\": \"Recombinant protein secretion assays, C3b degradation in plasma, zebrafish retinal vascular assay (for CFI variant); reconstituted proteolytic inactivation assay with purified proteins (for C3 variant)\",\n      \"pmids\": [\"23685748\", \"24036952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural determinants on C3b recognized by CFI during cleavage not defined\",\n        \"Whether substrate sequence variants affect all cofactor-dependent pathways equally is untested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that reduced circulating FI protein level—not merely genetic variant carrier status—is the proximate risk factor for AMD, establishing quantitative FI deficiency as the mechanistic driver.\",\n      \"evidence\": \"Serum FI ELISA in large cohort of rare CFI variant carriers and non-carriers, statistical association with advanced AMD risk\",\n      \"pmids\": [\"25788521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Threshold FI level below which complement dysregulation occurs not defined\",\n        \"Whether FI supplementation can rescue AMD phenotype untested\",\n        \"Tissue-specific (retinal) FI expression and its contribution not separated from circulating pool\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying the catalytic triad and systematically classifying variant effects: a homozygous His380Arg mutation directly confirmed His380 as part of the catalytic triad (His380/Asp429/Ser525), and systematic in vivo testing of 20 rare CFI variants stratified alleles by functional consequence, revealing that multiple rare hypoactive alleles contribute to AMD.\",\n      \"evidence\": \"Genetic sequencing and complement functional testing of catalytic triad mutant; zebrafish retinal vascularization assay screening 20 CFI variants\",\n      \"pmids\": [\"28942469\", \"28282489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only one catalytic triad residue mutation characterized; Asp429 and Ser525 mutations not yet reported in patients\",\n        \"Zebrafish assay is a surrogate; direct correspondence to human retinal complement regulation assumed but not proven\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing a mechanistic classification of CFI variant dysfunction: serum-based assays stratified rare variants into Type 1 (low antigen/low function), Type 2 (normal antigen/reduced cleavage), and Type 3 (normal antigen and cleavage/reduced specific activity), providing a comprehensive framework for genotype–mechanism correlation.\",\n      \"evidence\": \"Sandwich ELISA for FI antigen combined with Factor H-dependent C3b proteolytic cleavage assay in patient sera\",\n      \"pmids\": [\"32908800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis distinguishing Type 2 from Type 3 dysfunction not determined\",\n        \"Whether this classification predicts clinical severity or therapeutic response is untested\",\n        \"Assay uses only Factor H as cofactor; behavior with CR1 or C4BP cofactors not assessed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of the CFI–cofactor–C3b ternary complex exists, and the molecular basis for how cofactor binding activates CFI catalysis and directs substrate cleavage site specificity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of CFI in complex with cofactor and substrate\",\n        \"Allosteric mechanism by which cofactor binding activates the CFI serine protease domain unknown\",\n        \"Whether therapeutic FI supplementation can restore complement regulation in vivo not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CFH\",\n      \"C3b\",\n      \"C4b\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}