Complement factor I is a secreted regulatory serine protease that cleaves the complement fragments C3b and C4b in complexes with appropriate cofactors, including factor H, C4b-binding protein, CD46 and CR1. Its noncatalytic heavy chain and catalytic light chain are produced from one precursor and remain linked by a disulfide bond. The mature enzyme has a zymogen-like resting conformation; substrate and cofactor contacts stabilize a proteolytically competent state. Its limited cleavage prevents complement amplification and also generates fragments with distinct complement-receptor recognition properties. Factor I acts in extracellular fluids and can associate transiently with membrane-attached substrate/cofactor complexes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Factor I is a cofactor-dependent serine endopeptidase. Reason: The combined domain/EC mapping agrees with actual human factor-I structure and C3b cleavage assays. The catalytic light chain cleaves internal substrate peptide bonds; the heavy chain and substrate/cofactor contacts regulate access to the active conformation. The crystallized S525A ternary complex in PMID:28671664 is catalytically inactive and is distinguished from its separate active-FI cleavage experiments. |
| GO:0004252 serine-type endopeptidase activity | TAS PMID:2956252 Human complement factor I: analysis of cDNA-derived primary ... | ACCEPT | Summary: The original human cDNA reference supports the established serine-protease identity. Reason: The authentic abstract describes human 583-residue prepro-I and its cofactor-dependent cleavage of C3b/C4b. Full original Methods were not accessed, so this TAS is not presented as a newly inspected direct catalytic assay. Independent full human structural and biochemical studies establish the retained activity. |
| GO:0004252 serine-type endopeptidase activity | TAS PMID:8604219 cDNA cloning, sequencing and chromosomal assignment of the g... | ACCEPT | Summary: The conserved factor-I catalytic function is correct for human CFI. Reason: The authentic source abstract explicitly studies mouse cDNA and comparative mouse, human, Xenopus and chicken sequences; it also describes the human two-chain regulatory serine protease. Preserve the human TAS source as supplied. Human activity is independently supported by PMID:28671664, without claiming a human catalytic experiment in this mouse-focused paper or rejecting the annotation from its title. |
| GO:0005515 protein binding | IPI PMID:16237761 Screening of hepatocyte proteins binding to F protein of hep... | KEEP AS NON CORE | Summary: A human factor-I library clone was recovered with HCV F protein. Reason: The actual primary Table 1 reports one clone with 98% similarity to human factor-I mRNA in a GAL4 yeast-two-hybrid liver-library screen. Methods identify genotype 1b F bait; the preserved P0C045 partner identifies H77 genotype 1a, so exact strain/accession equivalence and the CFI insert boundaries remain unresolved. Follow-up co-IP tests FBP2, not CFI. Retain the supported generic association under the campaign binding instruction, without inferring endogenous encounter or a viral physiological function. |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | KEEP AS NON CORE | Summary: Tagged CFI associates with human GLP1R in screening and co-IP assays. Reason: Selected original Results explicitly place CFI among positive MYTH candidates and intermediate co-IP signals in CHO cells expressing human GLP1R-V5-His and HA-tagged prey. Exact positive IntAct records match P05156/P43220 and the yeast/CHO assay contexts. These engineered associations support non-core binding, not endogenous receptor regulation or purified binary affinity. CFI is not among the reported cAMP-suppressive candidates. |
| GO:0005576 extracellular region | EXP PMID:6327681 Biosynthesis and postsynthetic processing of human C3b/C4b i... | ACCEPT | Summary: Human factor I is secreted into the extracellular compartment. Reason: The authentic source abstract directly compares factor-I secretion and precursor processing in three human hepatoma cell lines. This supports the original EXP location. Different proportions of single-chain pro-I and processed two-chain I do not create separately seeded splice products; independent serum purification supports the extracellular protein. |
| GO:0005576 extracellular region | HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu... | ACCEPT | Summary: Extracellular localization remains correct in this human-colostrum proteomic assertion. Reason: The authentic abstract describes low-abundance proteins in the aqueous phase of human colostrum. Its exact CFI table entry was not independently recovered; retain the HDA source without claiming target-peptide verification. The same broad extracellular location is independently established by human hepatoma secretion and serum-derived factor I. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: The curated secretion-location mapping agrees with factor-I biology. Reason: The preserved UniProt SL-0112/SL-0243 mapping is concordant with the genuine source record and human secretion/serum purification. Factor I acts extracellularly, including on surface-attached substrates; this does not make it an integral membrane protein. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-3266557 | ACCEPT | Summary: CR1-assisted extracellular cleavage of iC3b Reason: The selected Reactome event describes CFI cleavage of iC3b with CR1, releasing C3c while C3dg remains membrane attached. This is an extracellular enzymatic reaction, consistent with the core secreted enzyme. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-976743 | ACCEPT | Summary: Extracellular processing of factor-H-bound C3b Reason: The selected plasma reaction identifies CFI cleavage of factor-H-bound C3b. Its location agrees with direct human serum and biochemical evidence. The cache wording that iC3b is proteolytically inactive is not used to imply that C3b itself is a protease. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-976801 | ACCEPT | Summary: The mature factor-I complex acts extracellularly Reason: The selected Reactome record describes the heavy/light-chain enzyme and its extracellular complement substrates/cofactors. Its complex-formation summary is provenance for the TAS location, not an independent microscopy experiment. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-976810 | ACCEPT | Summary: The factor-H:C3b encounter occurs extracellularly Reason: The selected event explicitly models CFI binding to extracellular factor-H:C3b. Human structural and biochemical evidence independently supports the substrate/cofactor encounter; the original TAS remains unchanged. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-977359 | ACCEPT | Summary: Surface-associated substrate binding remains extracellular Reason: The selected event forms a membrane-associated factor-H:C3b:CFI complex. Peripheral attachment to an extracellular substrate complex is compatible with this extracellular-region annotation; no transmembrane domain or permanent residency is inferred. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-977371 | ACCEPT | Summary: Cleavage of surface-bound C3b occurs extracellularly Reason: The selected event describes CFI cleavage after Bb displacement, yielding surface-bound iC3b. Factor I supplies proteolysis; the preceding convertase-decay step is not assigned to it from this event. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-977602 | ACCEPT | Summary: CD46/CR1 substrate complexes recruit extracellular factor I Reason: The selected event binds CFI to CD46/MCP or CR1 complexes with C3b/C4b. The protease remains on the extracellular side during these encounters. Preserve the source-specific TAS rather than recasting it as new direct localization evidence. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-977615 | ACCEPT | Summary: C4b cleavage is an extracellular factor-I reaction Reason: The selected event describes sequential C4b alpha-chain cleavage with release of fragments and retention of membrane-bound C4d. Its mechanistic compartment is consistent with secreted factor I. Source residue numbering is not independently reannotated here. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-981637 | ACCEPT | Summary: C4BP-supported C4b processing occurs extracellularly Reason: The selected event describes C4BP-assisted CFI cleavage, release of C4c and retention of C4d on the cell surface. This supports the extracellular compartment without making factor I a membrane-spanning component. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-981658 | ACCEPT | Summary: The C4BP cofactor encounter occurs extracellularly Reason: The selected event describes C4BP enabling CFI binding and C4b proteolysis. This extracellular substrate/cofactor context agrees with the independently established localization of the secreted enzyme. Supporting Evidence: Reactome:R-HSA-981658 allowing it to bind and thereby mediating C4b proteolysis |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | ACCEPT | Summary: CFI itself performs limited complement-substrate proteolysis. Reason: Human factor I cleaves internal C3b/C4b peptide bonds with regulatory cofactors. Separate biochemical cleavage assays support actual catalysis, not merely factor-I necessity in a phenotype or a substrate being cleaved. Limited regulatory processing is within proteolysis even when products retain new recognition functions. |
| GO:0006956 complement activation | IEA GO_REF:0000107 | MODIFY | Summary: Negative regulation specifies the principal complement role more accurately. Reason: The literal mouse Q61129/ENSMUSP00000077074 donor identity is sound. Human factor I directly cleaves C3b/C4b, preventing further convertase formation and amplification. GO:0045916 captures this negative regulatory work more precisely than broad complement activation. Preserve the original electronic source; this recommendation is not a new experimental annotation or an allegation of orthology error. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: UniProtKB:Q61129 SUPPORTS TRANSFER Official mouse Cfi identity and ENSMUSP00000077074.6 cross-reference are consistent with the unversioned source. Human direct mechanism supplies the directional refinement; the historical Compara run was not reconstructed. Proposed replacements: negative regulation of complement activation |
| GO:0008236 serine-type peptidase activity | IBA GO_REF:0000033 | MODIFY | Summary: Endopeptidase activity is the experimentally resolved serine-peptidase subtype. Reason: GO:0004252 is a current is_a descendant of GO:0008236 and describes cleavage of internal peptide bonds. Actual human substrate processing supports that specificity. Preserve every original PAINT donor and node; this does not challenge ancestral placement, infer weakness from donor diversity or convert IBA into pairwise similarity. The same specific activity is already supported by three retained annotations; this source-specific refinement improves precision without claiming new functional coverage. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN002543071 UNRESOLVED Historical ancestral placement, alignment and complete IBD evidence were not reconstructed. Independent target evidence is assessed without treating IBA as pairwise transfer or criticizing donor count. Proposed replacements: serine-type endopeptidase activity |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: The domain-based membrane assignment is broader than the localization evidence establishes. Reason: The literal InterPro sources are SRCR/IPR001190 and SRCR-like/IPR036772, found in secreted as well as membrane proteins; they do not establish a membrane-localized factor-I pool. The inspected human Reactome events describe recruitment of soluble CFI to surface-associated substrate/cofactor complexes, and retain extracellular-region context. Such catalytic encounters are real, but are insufficient here to retain the unqualified domain-derived located_in membrane inference. This source-specific overannotation judgment does not exclude indirect membrane association, demand direct lipid binding, or deny the current GO definition includes attached complexes. Supporting Evidence: Reactome:R-HSA-977359 Reactome:R-HSA-977602 file:human/CFI/CFI-source-evidence.json |
| GO:0016485 protein processing | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain broad functional protein processing with explicit maturation limits. Reason: GO:0016485 specifically concerns cleavage-mediated maturation toward full functional capacity. CFI cleavage inhibits C3b/C4b convertase functions, while iC3b/C3dg products have distinct complement-receptor recognition activities; thus the broader inherited processing assertion remains defensible, but the classical maturation sense is not the principal core role. Retain this source as non-core and state negative complement regulation in the core. This is neither a claim that cleavage only destroys function nor that CFI matures its own precursor. Historical PAINT node placement and the full IBD evidence were not reconstructed; donor identities do not establish why the assertion was placed. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002543071 UNRESOLVED Historical ancestral placement, alignment and complete IBD evidence were not reconstructed. Independent target evidence is assessed without treating IBA as pairwise transfer or criticizing donor count. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: The original urinary-exosome data resource contains a CFI identification. Reason: The authors' official NIH Urinary Exosome Protein Database lists CFI/NP_000195 with one peptide and reference 2, which identifies PMID:19056867. This independently recovers the target entry supporting the original HDA. Retain vesicle-preparation association as non-core; the row alone does not resolve luminal versus surface-associated protein, mature-chain state or a role in exosome biogenesis. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | UNDECIDED | Summary: The EPS-urine target-specific exosome assignment remains unverified. Reason: The full main paper describes pooled human EPS-urine vesicle proteomics, but its exact CFI entry in Supplemental Table 2 was not recovered. It also acknowledges possible soluble/blood-derived components in these preparations. The separate urinary-exosome target record supports a related context but does not independently establish the specific EPS-urine identification or topology here. Preserve the HDA assertion while leaving this source-specific assignment unresolved; no absence or false-curation claim is made. The sibling PMID:19056867 annotation is retained on its independently recovered, single-peptide author-table entry; it does not resolve this different preparation. |
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Download this section (compressed HTML)Q: What molecular form of factor I is present in urinary and EPS-urine vesicle preparations, and is it vesicle-luminal, surface-associated or a soluble co-isolate?
Q: Do the engineered HCV-F and GLP1R associations occur with sequence-defined mature human factor I in physiological cellular or extracellular contexts?
Experiment: Use orthogonal vesicle purification, peptide mapping and protease-protection assays with and without detergent to distinguish intact factor I and its chains, surface association, luminal cargo and soluble contamination.
Experiment: Test the reported partner associations using sequence-defined factor-I products and viral strain constructs, matched expression and secretion controls, and endogenous-context assays before assigning a downstream signaling or viral role.
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