Complement factor I

CFI
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2XRC
Identifiers
Aliases	CFI, AHUS3, ARMD13, C3BINA, C3b-INA, FI, IF, KAF, complement factor I
External IDs	OMIM: 217030; MGI: 105937; HomoloGene: 171; GeneCards: CFI; OMA:CFI - orthologs
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q25 Start 109,740,694 bp[1] End 109,802,179 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 G3|3 59.21 cM Start 129,629,533 bp[2] End 129,668,981 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in germinal epithelium parietal pleura right lobe of liver gallbladder palpebral conjunctiva visceral pleura kidney tubule human kidney right adrenal cortex caput epididymis Top expressed in left lobe of liver epithelium of stomach pyloric antrum gallbladder mucous cell of stomach fetal liver hematopoietic progenitor cell migratory enteric neural crest cell human fetus endocardial cushion yolk sac More reference expression data BioGPS n/a
Gene ontology Molecular function peptidase activity hydrolase activity serine-type peptidase activity metal ion binding serine-type endopeptidase activity scavenger receptor activity protein binding Cellular component extracellular exosome membrane extracellular region extracellular space Biological process complement activation, classical pathway regulation of complement activation receptor-mediated endocytosis proteolysis immune system process innate immune response viral process vesicle-mediated transport endocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3426 12630 Ensembl ENSG00000205403 ENSMUSG00000058952 UniProt P05156 Q8WW88 Q61129 RefSeq (mRNA) NM_000204 NM_001318057 NM_001331035 NM_007686 NM_001329552 RefSeq (protein) NP_000195 NP_001304986 NP_001317964 NP_001362207 NP_001362208 NP_001362209 NP_001362210 NP_001362211 NP_001362212 NP_001362213 NP_001304986.1 NP_001316481 NP_031712 Location (UCSC) Chr 4: 109.74 – 109.8 Mb Chr 3: 129.63 – 129.67 Mb PubMed search [3] [4]
Wikidata
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Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene. Complement factor I (factor I) is a protein of the complement system, first isolated in 1966 in guinea pig serum,^[5] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.^[6] It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.^[7]

The gene for Factor I in humans is located on chromosome 4.^[8] Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, keratinocytes, and endothelial cells.^[9][10][11] When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions.^[12] Then, factor I is cleaved by furin to yield the mature factor I protein, which is a disulfide-linked dimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton).^[13] Only the mature protein is active.

Factor I is a glycoprotein heterodimer consisting of a disulfide linked heavy chain and light chain.^[14]

The factor I heavy chain has four domains: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) domains.^[15] the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by the substrate (either C3b or C4b) and a cofactor protein (Factor H, C4b-binding protein, complement receptor 1, and membrane cofactor protein).^[16] Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery.^[16] The LDL-receptor domains contain one Calcium-binding site each.

The factor I light chain contains only the serine protease domain. This domain contains the catalytic triad His-362, Asp-411, and Ser-507, which is responsible for specific cleavage of C3b and C4b.^[15] Conventional protease inhibitors do not completely inactivate Factor I^[17] but they can do so if the enzyme is pre-incubated with its substrate: this supports the proposed rearrangement of the molecule upon binding to the substrate.

Both heavy and light chains bear Asn-linked glycans, on three distinct glycosylation sites each.

Crystal structure the crystal structure of human Factor I has been deposited as PDB: 2XRC.

Dysregulated factor I activity has clinical implications. Loss of function mutations in the Complement Factor I gene lead to low levels of factor I which results in increased complement activity. Factor I deficiency in turn leads to low levels of complement component 3 (C3), factor B, factor H and properdin in blood, due to unregulated activation of C3 convertase, and to low levels of IgG, due to loss of iC3b and C3dg production. In addition to the following diseases, low factor I is associated with recurrent bacterial infections in children.

Research suggests that mutations in the CFI gene contribute to development of age-related macular degeneration.^[18] This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.^[19]

Atypical hemolytic uremic syndrome is caused by complement overactivation.^[20] Heterozygous mutations in the serine protease domain of the CFI gene account for 5-10% of cases.^[20]

• GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
• OMIM entries on Atypical Hemolytic-Uremic Syndrome
• The MEROPS online database for peptidases and their inhibitors: S01.199