Complement factor I

Complement factor I
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2XRC​
Identifiers
Symbols	CFI ; AHUS3; C3BINA; C3b-INA; FI; IF; KAF
External IDs	OMIM: 217030 MGI: 105937 HomoloGene: 171 GeneCards: CFI Gene
EC number	3.4.21.45
Gene ontology Molecular function • serine-type endopeptidase activity • scavenger receptor activity • metal ion binding Cellular component • extracellular region • extracellular space • membrane Biological process • proteolysis • complement activation, classical pathway • regulation of complement activation • innate immune response Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3426	12630
Ensembl	ENSG00000205403	ENSMUSG00000058952
UniProt	P05156	Q61129
RefSeq (mRNA)	NM_000204	NM_007686
RefSeq (protein)	NP_000195	NP_031712
Location (UCSC)	Chr 4: 110.66 – 110.72 Mb	Chr 3: 129.84 – 129.88 Mb
PubMed search

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), factor B, factor H and properdin.^[5] in plasma, due to unregulated activation of C3 convertase,^[6] and to low levels of IgG, due to loss of iC3b and C3dg production^[6][7][8] It has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated^[9] 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.^[10] 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^[11] 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^[12] and recently explained in terms of variants R201S, R406H, R502L.^[13]

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

References

1. "Entrez Gene: complement factor I".
2. 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. PMID 2956252.
3. 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. PMID 5960883.
4. 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. PMID 5645214.
5. Grumach AS, Leitão MF, Arruk VG, Kirschfink M, Condino-Neto A (Feb 2006). "Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family". Clinical and Experimental Immunology 143 (2): 297–304. doi:10.1111/j.1365-2249.2005.02988.x. PMID 16412054.
6. González-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. PMID 11709004.
7. 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. PMID 7922290.
8. 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. PMID 9476132.
9. 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. PMID 17089378.
10. Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM (Aug 2011). "Structural basis for complement factor I control and its disease-associated sequence polymorphisms". Proceedings of the National Academy of Sciences of the United States of America 108 (31): 12839–44. doi:10.1073/pnas.1102167108. PMC 3150940. PMID 21768352.
11. ,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. PMID 2140392.
12. Nakamura S, Abe K (1985). "Genetic polymorphism of human factor I (C3b inactivator)". Human Genetics 71 (1): 45–8. doi:10.1007/BF00295667. PMID 3897024.
13. 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. PMID 18825487.

Further reading

• Bradley DT, Zipfel PF, Hughes AE (Jun 2011). "Complement in age-related macular degeneration: a focus on function". Eye 25 (6): 683–93. doi:10.1038/eye.2011.37. PMC 3178140. PMID 21394116.
• Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD (Feb 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. doi:10.1053/j.ajkd.2008.06.027. PMC 2879708. 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 (Jun 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. doi:10.1093/hmg/ddq112. PMC 2876884. PMID 20332099.
• 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. 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. doi:10.2119/molmed.2009.00159. PMC 2896464. 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 (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. PMID 20059470.
• 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. 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 (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. PMID 20016463.
• Kondo N, Bessho H, Honda S, Negi A (Jun 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. doi:10.1038/ejhg.2009.243. PMC 2987347. PMID 20087399.
• 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. PMID 20513133.
• Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM (Dec 2009). "Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes". Investigative Ophthalmology & Visual Science 50 (12): 5818–27. doi:10.1167/iovs.09-3928. PMC 2826794. PMID 19661236.
• Shin DH, Webb BM, Nakao M, Smith SL (Jul 2009). "Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence". Molecular Immunology 46 (11-12): 2299–308. doi:10.1016/j.molimm.2009.04.002. PMC 2699631. 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 (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. PMID 19065647.
• Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM (Jan 2009). "Variation near complement factor I is associated with risk of advanced AMD". European Journal of Human Genetics 17 (1): 100–4. doi:10.1038/ejhg.2008.140. PMC 2985963. PMID 18685559.
• 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. PMID 19693526.
• 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 (Jan 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.
• 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. PMID 18701018.
• Nilsson SC, Nita I, Månsson L, Groeneveld TW, Trouw LA, Villoutreix BO, Blom AM (Feb 2010). "Analysis of binding sites on complement factor I that are required for its activity". The Journal of Biological Chemistry 285 (9): 6235–45. doi:10.1074/jbc.M109.097212. PMC 2825419. 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