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 in development of Haemolytic Uremic Syndrome, a renal disease also caused by unregulated complement activation.
The gene for Factor I in humans is located on chromosome 4. 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-linkeddimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton). Only the mature protein is active.
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. 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 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.
^ abGoldberger 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. PMID2956252.
^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". Immunochemistry3 (2): 111–35. doi:10.1016/0019-2791(66)90292-8. PMID5960883.
^Lachmann P, Müller-Eberhard H (1968). "The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement". Journal of Immunology100 (4): 691–8. PMID5645214.
^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 Mutat28 (3): 222–34. doi:10.1002/humu.20435. PMID17089378.
^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)". PNAS108 (31): 12839–12844. doi:10.1073/pnas.1102167108. PMC3150940. PMID21768352.
^,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". Journal of Immunologyogy144 (11): 4269–74. PMID2140392.
^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". Journal of Human Genetics53 (11–12): 1016–21. doi:10.1007/s10038-008-0337-4. PMID18825487.
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. PMC2879708. PMID18805611.
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. PMC2876884. PMID20332099.
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. PMID19877009.
Sullivan M, Erlic Z, Hoffmann MM, et al. (2010). "Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome". Annals of Human Genetics74 (1): 17–26. doi:10.1111/j.1469-1809.2009.00554.x. PMID20059470.
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. PMC2867722. PMID20385819.
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. PMID20106822.
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. PMID20016463.
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". European Journal of Human Genetics18 (6): 634–5. doi:10.1038/ejhg.2009.243. PMC2987347. PMID20087399.
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. PMID20513133.
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. PMC2826794. PMID19661236.
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. PMID19693526.
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". Blood115 (2): 379–87. doi:10.1182/blood-2009-05-221549. PMC2829859. PMID19861685.
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. PMID18701018.