Complement factor I explained

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,^[1] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.^[2] It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.^[3]

Synthesis

The gene for Factor I in humans is located on chromosome 4.^[4] Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, keratinocytes, and endothelial cells.^{[5] [6] [7]} When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions.^[8] Then, factor I is cleaved by furin to yield the mature factor I protein, which is a disulfide-linked dimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton).^[9] Only the mature protein is active.

Structure

Factor I is a glycoprotein heterodimer consisting of a disulfide linked heavy chain and light chain.^[10]

The factor I heavy chain has four domains: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) domains.^[11] 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, C4b-binding protein, complement receptor 1, and membrane cofactor protein).^[12] Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery.^[12] 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. Conventional protease inhibitors do not completely inactivate Factor I^[13] 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 Asn-linked 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 complement component 3 (C3), factor B, 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.

Age-related macular degeneration

Research suggests that mutations in the CFI gene contribute to development of age-related macular degeneration.^[14] This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.^[15]

Atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome is caused by complement overactivation.^[16] Heterozygous mutations in the serine protease domain of the CFI gene account for 5-10% of cases.

Further reading

• Bradley DT, Zipfel PF, Hughes AE . Complement in age-related macular degeneration: a focus on function . Eye . 25 . 6 . 683–93 . June 2011 . 21394116 . 3178140 . 10.1038/eye.2011.37 .
• Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD . 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 . February 2009 . 18805611 . 2879708 . 10.1053/j.ajkd.2008.06.027 .
• 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 . 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 . June 2010 . 20332099 . 2876884 . 10.1093/hmg/ddq112 .
• Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM . 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 . January 2010 . 19877009 . 10.1002/eji.200939280 . free .
• Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR . Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score . Molecular Medicine . 16 . 7–8 . 247–53 . 2010 . 20379614 . 2896464 . 10.2119/molmed.2009.00159 .
• 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 . Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome . Annals of Human Genetics . 74 . 1 . 17–26 . January 2010 . 20059470 . 10.1111/j.1469-1809.2009.00554.x . 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 . Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS) . Nephrology, Dialysis, Transplantation . 25 . 7 . 2195–202 . July 2010 . 20106822 . 10.1093/ndt/gfq010 . free .
• 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 . Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome . Kidney International . 77 . 4 . 339–49 . February 2010 . 20016463 . 10.1038/ki.2009.472 . free .
• Kondo N, Bessho H, Honda S, Negi A . 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 . June 2010 . 20087399 . 2987347 . 10.1038/ejhg.2009.243 .
• Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ . Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome . Human Mutation . 31 . 6 . E1445–60 . June 2010 . 20513133 . 10.1002/humu.21256 . 205919773 . free .
• Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM . Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes . Investigative Ophthalmology & Visual Science . 50 . 12 . 5818–27 . December 2009 . 19661236 . 2826794 . 10.1167/iovs.09-3928 .
• Shin DH, Webb BM, Nakao M, Smith SL . Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence . Molecular Immunology . 46 . 11–12 . 2299–308 . July 2009 . 19423168 . 2699631 . 10.1016/j.molimm.2009.04.002 .
• Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, Marquart H, Muller K, Sjöholm AG, Truedsson L, Villoutreix BO, Blom AM . Genetic, molecular and functional analyses of complement factor I deficiency . European Journal of Immunology . 39 . 1 . 310–23 . January 2009 . 19065647 . 10.1002/eji.200838702 . 8445601 . free .
• Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM . Variation near complement factor I is associated with risk of advanced AMD . European Journal of Human Genetics . 17 . 1 . 100–4 . January 2009 . 18685559 . 2985963 . 10.1038/ejhg.2008.140 .
• Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J . A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles . International Journal of Legal Medicine . 125 . 1 . 121–5 . January 2011 . 19693526 . 10.1007/s00414-009-0369-0 . 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 . 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 . January 2010 . 19861685 . 2829859 . 10.1182/blood-2009-05-221549 .
• Li MZ, Yu DM, Yu P, Liu DM, Wang K, Tang XZ . Mitochondrial gene mutations and type 2 diabetes in Chinese families . Chinese Medical Journal . 121 . 8 . 682–6 . April 2008 . 18701018 . 10.1097/00029330-200804020-00004. free .
• Nilsson SC, Nita I, Månsson L, Groeneveld TW, Trouw LA, Villoutreix BO, Blom AM . Analysis of binding sites on complement factor I that are required for its activity . The Journal of Biological Chemistry . 285 . 9 . 6235–45 . February 2010 . 20044478 . 2825419 . 10.1074/jbc.M109.097212 . free .

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

Notes and References

1. Nelson RA, Jensen J, Gigli I, Tamura N . Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum . Immunochemistry . 3 . 2 . 111–35 . March 1966 . 5960883 . 10.1016/0019-2791(66)90292-8 .
2. Lachmann PJ, Müller-Eberhard HJ . 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 . April 1968 . 10.4049/jimmunol.100.4.691 . 5645214 . free .
3. Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM . Complement factor I in health and disease . Molecular Immunology . 48 . 14 . 1611–20 . August 2011 . 21529951 . 10.1016/j.molimm.2011.04.004 . 37521895 . Submitted manuscript .
4. Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ . 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 . July 1987 . 10.1016/S0021-9258(18)61076-2 . 2956252 . free .
5. Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, Walport MJ . The molecular basis of hereditary complement factor I deficiency . The Journal of Clinical Investigation . 97 . 4 . 925–33 . February 1996 . 8613545 . 10.1172/JCI118515 . 507137 .
6. Julen N, Dauchel H, Lemercier C, Sim RB, Fontaine M, Ripoche J . In vitro biosynthesis of complement factor I by human endothelial cells . European Journal of Immunology . 22 . 1 . 213–7 . January 1992 . 1530917 . 10.1002/eji.1830220131. 30130789 .
7. Whaley K . Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes . The Journal of Experimental Medicine . 151 . 3 . 501–16 . March 1980 . 6444659 . 2185797 . 10.1084/jem.151.3.501 .
8. Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, Dwek RA, Rudd PM, Sim RB . Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1764 . 11 . 1757–66 . November 2006 . 17055788 . 10.1016/j.bbapap.2006.09.007 . 10.1.1.712.1764 .
9. Web site: FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2018-03-30.
10. Web site: CFI complement factor I [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2018-03-27.
11. Sanchez-Gallego JI, Groeneveld TW, Krentz S, Nilsson SC, Villoutreix BO, Blom AM . Analysis of binding sites on complement factor I using artificial N-linked glycosylation . The Journal of Biological Chemistry . 287 . 17 . 13572–83 . April 2012 . 22393059 . 3340171 . 10.1074/jbc.M111.326298 . free .
12. Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM . 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 . August 2011 . 21768352 . 3150940 . 10.1073/pnas.1102167108 . 2011PNAS..10812839R . free .
13. Ekdahl KN, Nilsson UR, Nilsson B . 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 . June 1990 . 10.4049/jimmunol.144.11.4269 . 2140392 . free .
14. Wang Q, Zhao HS, Li L . Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration: a Meta-analysis of literature . International Journal of Ophthalmology . 9 . 2 . 298–305 . 2016-02-18 . 26949655 . 4761747 . 10.18240/ijo.2016.02.23 .
15. Tan PL, Garrett ME, Willer JR, Campochiaro PA, Campochiaro B, Zack DJ, Ashley-Koch AE, Katsanis N . Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration . Investigative Ophthalmology & Visual Science . 58 . 3 . 1570–1576 . March 2017 . 28282489 . 6022411 . 10.1167/iovs.16-20867 .
16. Kavanagh D, Goodship TH, Richards A . Atypical hemolytic uremic syndrome . Seminars in Nephrology . 33 . 6 . 508–30 . November 2013 . 24161037 . 3863953 . 10.1016/j.semnephrol.2013.08.003 .