Complement factor I
Complement factor I, also known as C3B/C4B inactivator, is a protein that in humans is encoded by the CFI gene.[1][2]
Complement Factor I (fI) is a protein of the complement system, first isolated in 1966 in guinea pig serum[3] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.[4]
Pathology
Factor I deficiency in turn leads to low levels of complement component 3 (C3) in plasma, due to unregulated activation of the complement alternative pathway, and it has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated[5] in development of Haemolytic Uremic Syndrome, a renal disease also caused by unregulated complement activation.
Synthesis
The gene for Factor I in humans is located on chromosome 4.[2] Factor I is synthesised mostly in the liver, and is initially secreted as a single 88 kDalton gene product; this precursor protein is then cleaved by furin to yield the mature fI protein, which is a disulfide-linked dimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton). Only the mature protein is active.
Structure
Both heavy and light chains bear Asn-linked glycans, on three distinct glycosylation sites each.
The fI heavy chain has four domains: a FIMAC domain, a Scavenger Receptor Cysteine Rich (SRCR) domain and two LDL-receptor Class A domains; 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, CR1, MCP or C4BP). Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery [6] . The LDL-receptor domains contain one Calcium-binding site each.
The fI light chain is the serine protease domain containing the catalytic triad responsible for specific cleavage of C3b and C4b. Conventional protease inhibitors do not completely inactivate Factor I[7] 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.
Genetic polymorphism in Factor I has been observed[8] and recently explained in terms of variants R201S, R406H, R502L.[9]
Crystal structure the crystal structure of human Factor I has been deposited as PDB 2XRC.
References
- ^ "Entrez Gene: complement factor I". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3426.
- ^ a b Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ (July 1987). "Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4". J. Biol. Chem. 262 (21): 10065–71. PMID 2956252.
- ^ Nelson R, Jensen J, Gigli I, Tamura N (1966). "Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum". Immunochemistry 3 (2): 111–35. doi:10.1016/0019-2791(66)90292-8. PMID 5960883.
- ^ Lachmann P, Müller-Eberhard H (1968). "The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement". J Immunol 100 (4): 691–8. PMID 5645214.
- ^ Saunders R, Abarrategui-Garrido C, Frémeaux-Bacchi V, Goicoechea de Jorge E, Goodship T, López Trascasa M, Noris M, Ponce Castro I, Remuzzi G, Rodríguez de Córdoba S, Sánchez-Corral P, Skerka C, Zipfel P, Perkins S (2007). "The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models". Hum Mutat 28 (3): 222–34. doi:10.1002/humu.20435. PMID 17089378.
- ^ Roversi P, Johnson S, Caesar JJE, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SML (2011). "Structural basis for complement factor I control and its disease-associated sequence polymorphisms)". PNAS 108 (31): 12839–12844. PMID 21768352.
- ^ ,Ekdahl KN, Nilsson UR, Nilsson B. (1990). "Inhibition of factor I by diisopropylfluorophosphate. Evidence of conformational changes in factor I induced by C3b and additional studies on the specificity of factor I". J. Immunology 144 (11): 4269–74. PMID 2140392.
- ^ Nakamura S, Abe K (1985). "Genetic polymorphism of human factor I (C3b inactivator)". Hum Genet 71 (1): 45–8. doi:10.1007/BF00295667. PMID 3897024.
- ^ Yuasa I et al. (2008). "Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific". J. Hum Genet 53 (11–12): 1016–21. doi:10.1007/s10038-008-0337-4. PMID 18825487.
Further reading
- Bradley, D T; Zipfel, P F; Hughes, A E (2011). "Complement in age-related macular degeneration: a focus on function". Eye 25 (6). doi:10.1038/eye.2011.37. PMC 3178140. PMID 21394116. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3178140.
- Chan MR, Thomas CP, Torrealba JR, et al. (2009). "Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient". Am. J. Kidney Dis. 53 (2): 321–6. doi:10.1053/j.ajkd.2008.06.027. PMC 2879708. PMID 18805611. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2879708.
- Kalsi G, Kuo PH, Aliev F, et al. (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". Hum. Mol. Genet. 19 (12): 2497–506. doi:10.1093/hmg/ddq112. PMC 2876884. PMID 20332099. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2876884.
- Nilsson SC, Kalchishkova N, Trouw LA, et al. (2010). "Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I". Eur. J. Immunol. 40 (1): 172–85. doi:10.1002/eji.200939280. PMID 19877009.
- Rose JE, Behm FM, Drgon T, et al. (2010). "Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score". Mol. Med. 16 (7–8): 247–53. doi:10.2119/molmed.2009.00159. PMC 2896464. PMID 20379614. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2896464.
- Sullivan M, Erlic Z, Hoffmann MM, et al. (2010). "Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome". Ann. Hum. Genet. 74 (1): 17–26. doi:10.1111/j.1469-1809.2009.00554.x. PMID 20059470.
- Chen W, Stambolian D, Edwards AO, et al. (2010). "Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration". Proc. Natl. Acad. Sci. U.S.A. 107 (16): 7401–6. doi:10.1073/pnas.0912702107. PMC 2867722. PMID 20385819. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2867722.
- Westra D, Volokhina E, van der Heijden E, et al. (2010). "Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)". Nephrol. Dial. Transplant. 25 (7): 2195–202. doi:10.1093/ndt/gfq010. PMID 20106822.
- Bienaime F, Dragon-Durey MA, Regnier CH, et al. (2010). "Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome". Kidney Int. 77 (4): 339–49. doi:10.1038/ki.2009.472. PMID 20016463.
- Kondo N, Bessho H, Honda S, Negi A (2010). "Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration". Eur. J. Hum. Genet. 18 (6): 634–5. doi:10.1038/ejhg.2009.243. PMC 2987347. PMID 20087399. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2987347.
- Maga TK, Nishimura CJ, Weaver AE, et al. (2010). "Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome". Hum. Mutat. 31 (6): E1445–60. doi:10.1002/humu.21256. PMID 20513133.
- Reynolds R, Hartnett ME, Atkinson JP, et al. (2009). "Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes". Invest. Ophthalmol. Vis. Sci. 50 (12): 5818–27. doi:10.1167/iovs.09-3928. PMC 2826794. PMID 19661236. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2826794.
- Shin DH, Webb BM, Nakao M, Smith SL (2009). "Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence". Mol. Immunol. 46 (11–12): 2299–308. doi:10.1016/j.molimm.2009.04.002. PMC 2699631. PMID 19423168. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2699631.
- Nilsson SC, Trouw LA, Renault N, et al. (2009). "Genetic, molecular and functional analyses of complement factor I deficiency". Eur. J. Immunol. 39 (1): 310–23. doi:10.1002/eji.200838702. PMID 19065647.
- Fagerness JA, Maller JB, Neale BM, et al. (2009). "Variation near complement factor I is associated with risk of advanced AMD". Eur. J. Hum. Genet. 17 (1): 100–4. doi:10.1038/ejhg.2008.140. PMC 2985963. PMID 18685559. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2985963.
- Yuasa I, Irizawa Y, Nishimukai H, et al. (2009). "A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles". Int. J. Legal Med. 125 (1): HASH(0x2b9aff824bb0). doi:10.1007/s00414-009-0369-0. PMID 19693526.
- Moore I, Strain L, Pappworth I, et al. (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. doi:10.1182/blood-2009-05-221549. PMC 2829859. PMID 19861685. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2829859.
- Li MZ, Yu DM, Yu P, et al. (2008). "Mitochondrial gene mutations and type 2 diabetes in Chinese families". Chin. Med. J. 121 (8): 682–6. PMID 18701018.
- Nilsson SC, Nita I, MÃ¥nsson L, et al. (2010). "Analysis of binding sites on complement factor I that are required for its activity". J. Biol. Chem. 285 (9): 6235–45. doi:10.1074/jbc.M109.097212. PMC 2825419. PMID 20044478. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2825419.
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