Complement factor I
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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]
Synthesis
The
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.
Structure
Factor I is a glycoprotein
heterodimer consisting of a disulfide linked heavy chain and light chain.[14]
The factor I heavy chain has four
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
glycans, on three distinct glycosylation
sites each.
Crystal structure the crystal structure of human Factor I has been deposited as PDB: 2XRC.
Clinical significance
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
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
Heterozygous mutations in the serine protease domain of the CFI gene account for 5-10% of cases.[20]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000205403 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000058952 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 5960883.
- PMID 5645214.
- S2CID 37521895.
- PMID 2956252.
- PMID 8613545.
- S2CID 30130789.
- PMID 6444659.
- PMID 17055788.
- ^ "FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-30.
- ^ "CFI complement factor I [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-27.
- ^ PMID 22393059.
- ^ PMID 21768352.
- PMID 2140392.
- PMID 26949655.
- PMID 28282489.
- ^ PMID 24161037.
Further reading
- Bradley DT, Zipfel PF, Hughes AE (June 2011). "Complement in age-related macular degeneration: a focus on function". Eye. 25 (6): 683–93. PMID 21394116.
- Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD (February 2009). "Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient". American Journal of Kidney Diseases. 53 (2): 321–6. PMID 18805611.
- Kalsi G, Kuo PH, Aliev F, Alexander J, McMichael O, Patterson DG, Walsh D, Zhao Z, Schuckit M, Nurnberger J, Edenberg H, Kramer J, Hesselbrock V, Tischfield JA, Vladimirov V, Prescott CA, Dick DM, Kendler KS, Riley BP (June 2010). "A systematic gene-based screen of chr4q22-q32 identifies association of a novel susceptibility gene, DKK2, with the quantitative trait of alcohol dependence symptom counts". Human Molecular Genetics. 19 (12): 2497–506. PMID 20332099.
- Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM (January 2010). "Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I". European Journal of Immunology. 40 (1): 172–85. PMID 19877009.
- Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR (2010). "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score". Molecular Medicine. 16 (7–8): 247–53. PMID 20379614.
- Sullivan M, Erlic Z, Hoffmann MM, Arbeiter K, Patzer L, Budde K, Hoppe B, Zeier M, Lhotta K, Rybicki LA, Bock A, Berisha G, Neumann HP (January 2010). "Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome" (PDF). Annals of Human Genetics. 74 (1): 17–26. S2CID 24304765.
- Westra D, Volokhina E, van der Heijden E, Vos A, Huigen M, Jansen J, van Kaauwen E, van der Velden T, van de Kar N, van den Heuvel L (July 2010). "Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)". Nephrology, Dialysis, Transplantation. 25 (7): 2195–202. PMID 20106822.
- Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautés-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V (February 2010). "Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome". Kidney International. 77 (4): 339–49. PMID 20016463.
- Kondo N, Bessho H, Honda S, Negi A (June 2010). "Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration". European Journal of Human Genetics. 18 (6): 634–5. PMID 20087399.
- Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ (June 2010). "Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome". Human Mutation. 31 (6): E1445–60. S2CID 205919773.
- Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM (December 2009). "Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes". Investigative Ophthalmology & Visual Science. 50 (12): 5818–27. PMID 19661236.
- Shin DH, Webb BM, Nakao M, Smith SL (July 2009). "Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence". Molecular Immunology. 46 (11–12): 2299–308. PMID 19423168.
- Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, Marquart H, Muller K, Sjöholm AG, Truedsson L, Villoutreix BO, Blom AM (January 2009). "Genetic, molecular and functional analyses of complement factor I deficiency". European Journal of Immunology. 39 (1): 310–23. S2CID 8445601.
- Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM (January 2009). "Variation near complement factor I is associated with risk of advanced AMD". European Journal of Human Genetics. 17 (1): 100–4. PMID 18685559.
- Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J (January 2011). "A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles". International Journal of Legal Medicine. 125 (1): 121–5. S2CID 37565572.
- Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ (January 2010). "Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome". Blood. 115 (2): 379–87. PMID 19861685.
- Li MZ, Yu DM, Yu P, Liu DM, Wang K, Tang XZ (April 2008). "Mitochondrial gene mutations and type 2 diabetes in Chinese families". Chinese Medical Journal. 121 (8): 682–6. PMID 18701018.
- Nilsson SC, Nita I, Månsson L, Groeneveld TW, Trouw LA, Villoutreix BO, Blom AM (February 2010). "Analysis of binding sites on complement factor I that are required for its activity". The Journal of Biological Chemistry. 285 (9): 6235–45. PMID 20044478.
External links
- 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[permanent dead link]
