Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFIgene. Complement factor I (fI) is a protein of the complement system, first isolated in 1966 in guinea pigserum,[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 plasma at an average concentration of 35 μg/mL.[7]
Pathology
Factor I deficiency in turn leads to low levels of complement component 3 (C3), factor B, factor H and properdin.[8] in plasma, due to unregulated activation of C3 convertase,[9] and to low levels of IgG, due to loss of iC3b and C3dg production[9][10][11] It has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated[12] 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.[13] Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, kerationcytes, and endothelial cells. [14][15][16] When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions. [17] Then, fI is 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).[18] . 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.[19] 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[20] 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[21] and recently explained in terms of variants R201S, R406H, R502L.[22]
^"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.
^Nelson RA, Jensen J, Gigli I, Tamura N (Mar 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. PMID5960883.
^Lachmann PJ, Müller-Eberhard HJ (Apr 1968). "The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement". Journal of Immunology. 100 (4): 691–8. PMID5645214.
^ abGonzález-Rubio C, Ferreira-Cerdán A, Ponce IM, Arpa J, Fontán G, López-Trascasa M (Nov 2001). "Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation". Archives of Neurology. 58 (11): 1923–8. doi:10.1001/archneur.58.11.1923. PMID11709004.
^Vyse TJ, Späth PJ, Davies KA, Morley BJ, Philippe P, Athanassiou P, Giles CM, Walport MJ (Jul 1994). "Hereditary complement factor I deficiency". QJM. 87 (7): 385–401. PMID7922290.
^Leitão MF, Vilela MM, Rutz R, Grumach AS, Condino-Neto A, Kirschfink M (Dec 1997). "Complement factor I deficiency in a family with recurrent infections". Immunopharmacology. 38 (1–2): 207–13. doi:10.1016/s0162-3109(97)00080-5. PMID9476132.
^Saunders RE, Abarrategui-Garrido C, Frémeaux-Bacchi V, Goicoechea de Jorge E, Goodship TH, López Trascasa M, Noris M, Ponce Castro IM, Remuzzi G, Rodríguez de Córdoba S, Sánchez-Corral P, Skerka C, Zipfel PF, Perkins SJ (Mar 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". Human Mutation. 28 (3): 222–34. doi:10.1002/humu.20435. PMID17089378.
^Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ (Jul 1987). "Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4". The Journal of Biological Chemistry. 262 (21): 10065–71. PMID2956252.
^,Ekdahl KN, Nilsson UR, Nilsson B (Jun 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 Immunology. 144 (11): 4269–74. PMID2140392.
^Nakamura S, Abe K (1985). "Genetic polymorphism of human factor I (C3b inactivator)". Human Genetics. 71 (1): 45–8. doi:10.1007/BF00295667. PMID3897024.
^Yuasa I, Nakagawa M, Umetsu K, Harihara S, Matsusue A, Nishimukai H, Fukumori Y, Saitou N, Park KS, Jin F, Lucotte G, Chattopadhyay PK, Henke L, Henke J (2008). "Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific". Journal of Human Genetics. 53 (11–12): 1016–21. doi:10.1007/s10038-008-0337-4. PMID18825487.
Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM (Jan 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. doi:10.1002/eji.200939280. PMID19877009.
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 (Jan 2010). "Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome". Annals of Human Genetics. 74 (1): 17–26. doi:10.1111/j.1469-1809.2009.00554.x. PMID20059470.
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 (Jul 2010). "Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS)". Nephrology, Dialysis, Transplantation. 25 (7): 2195–202. doi:10.1093/ndt/gfq010. PMID20106822.
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 (Feb 2010). "Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome". Kidney International. 77 (4): 339–49. doi:10.1038/ki.2009.472. PMID20016463.
Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ (Jun 2010). "Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome". Human Mutation. 31 (6): E1445-60. doi:10.1002/humu.21256. PMID20513133.
Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, Marquart H, Muller K, Sjöholm AG, Truedsson L, Villoutreix BO, Blom AM (Jan 2009). "Genetic, molecular and functional analyses of complement factor I deficiency". European Journal of Immunology. 39 (1): 310–23. doi:10.1002/eji.200838702. PMID19065647.
Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J (Jan 2011). "A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles". International Journal of Legal Medicine. 125 (1): 121–5. doi:10.1007/s00414-009-0369-0. PMID19693526.
Li MZ, Yu DM, Yu P, Liu DM, Wang K, Tang XZ (Apr 2008). "Mitochondrial gene mutations and type 2 diabetes in Chinese families". Chinese Medical Journal. 121 (8): 682–6. PMID18701018.
