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{{Infobox_gene}}
{{Infobox_gene}}


'''Complement factor I''', also known as '''C3b/C4b inactivator''', is a [[protein]] that in humans is encoded by the ''CFI'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: complement factor I| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3426| accessdate = }}</ref><ref name="pmid2956252">{{cite journal | vauthors = Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ | title = Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4 | journal = The Journal of Biological Chemistry | volume = 262 | issue = 21 | pages = 10065–71 | date = Jul 1987 | pmid = 2956252 | doi = }}</ref>
'''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]] [[blood plasma|serum]],<ref>{{cite journal | vauthors = Nelson RA, Jensen J, Gigli I, Tamura N | title = Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum | journal = Immunochemistry | volume = 3 | issue = 2 | pages = 111–35 | date = March 1966 | pmid = 5960883 | doi = 10.1016/0019-2791(66)90292-8 }}</ref> that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.<ref>{{cite journal | vauthors = Lachmann PJ, Müller-Eberhard HJ | title = The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement | journal = Journal of Immunology | volume = 100 | issue = 4 | pages = 691–8 | date = April 1968 | pmid = 5645214 }}</ref> It is a soluble [[glycoprotein]] that circulates in human blood at an average concentration of 35 μg/mL.<ref>{{cite journal | vauthors = Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM | title = Complement factor I in health and disease | journal = Molecular Immunology | volume = 48 | issue = 14 | pages = 1611–20 | date = August 2011 | pmid = 21529951 | doi = 10.1016/j.molimm.2011.04.004 | url = http://lup.lub.lu.se/record/1973336 | type = Submitted manuscript }}</ref>


Complement factor I (fI) is a protein of the [[complement system]], first isolated in 1966 in [[guinea pig]] [[blood plasma|serum]],<ref>{{cite journal | vauthors = Nelson RA, Jensen J, Gigli I, Tamura N | title = Methods for the separation, purification and measurement of nine components of hemolytic complement in guinea-pig serum | journal = Immunochemistry | volume = 3 | issue = 2 | pages = 111–35 | date = Mar 1966 | pmid = 5960883 | doi = 10.1016/0019-2791(66)90292-8 }}</ref> that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.<ref>{{cite journal | vauthors = Lachmann PJ, Müller-Eberhard HJ | title = The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement | journal = Journal of Immunology | volume = 100 | issue = 4 | pages = 691–8 | date = Apr 1968 | pmid = 5645214 }}</ref>
== Synthesis ==
The [[gene]] for Factor I in humans is located on [[chromosome 4]].<ref name="pmid2956252">{{cite journal | vauthors = Goldberger G, Bruns GA, Rits M, Edge MD, Kwiatkowski DJ | title = Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4 | journal = The Journal of Biological Chemistry | volume = 262 | issue = 21 | pages = 10065–71 | date = July 1987 | pmid = 2956252 | doi =  }}</ref> Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, keratinocytes, and endothelial cells.<ref>{{cite journal | vauthors = Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, Walport MJ | title = The molecular basis of hereditary complement factor I deficiency | journal = The Journal of Clinical Investigation | volume = 97 | issue = 4 | pages = 925–33 | date = February 1996 | pmid = 8613545 | doi = 10.1172/JCI118515 | pmc = 507137 }}</ref><ref>{{cite journal | vauthors = Julen N, Dauchel H, Lemercier C, Sim RB, Fontaine M, Ripoche J | title = In vitro biosynthesis of complement factor I by human endothelial cells | journal = European Journal of Immunology | volume = 22 | issue = 1 | pages = 213–7 | date = January 1992 | pmid = 1530917 | doi = 10.1002/eji.1830220131}}</ref><ref>{{cite journal | vauthors = Whaley K | title = Biosynthesis of the complement components and the regulatory proteins of the alternative complement pathway by human peripheral blood monocytes | journal = The Journal of Experimental Medicine | volume = 151 | issue = 3 | pages = 501–16 | date = March 1980 | pmid = 6444659 | pmc = 2185797 | doi = 10.1084/jem.151.3.501 }}</ref> When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions.<ref>{{cite journal | vauthors = Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, Dwek RA, Rudd PM, Sim RB | title = Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides | journal = Biochimica et Biophysica Acta | volume = 1764 | issue = 11 | pages = 1757–66 | date = November 2006 | pmid = 17055788 | doi = 10.1016/j.bbapap.2006.09.007 | citeseerx = 10.1.1.712.1764 }}</ref> Then, factor I is cleaved by [[furin]] to yield the mature factor I protein, which is a [[Disulfide bond|disulfide-linked]] [[Protein dimer|dimer]] of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton).<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/5045|title=FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-03-30}}</ref> Only the mature protein is active.


== Pathology ==
== Structure ==
Factor I is a glycoprotein [[heterodimer]] consisting of a disulfide linked heavy chain and light chain.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/3426|title=CFI complement factor I [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-03-27}}</ref>


Factor I deficiency in turn leads to low levels of [[C3 (complement)|complement component 3]] (C3), [[complement factor B|factor B]], [[complement factor H|factor H]] and [[properdin]].<ref>{{cite journal | vauthors = Grumach AS, Leitão MF, Arruk VG, Kirschfink M, Condino-Neto A | title = Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family | journal = Clinical and Experimental Immunology | volume = 143 | issue = 2 | pages = 297–304 | date = Feb 2006 | pmid = 16412054 | doi = 10.1111/j.1365-2249.2005.02988.x | pmc=1809586}}</ref> in plasma, due to unregulated activation of [[C3 convertase]],<ref name=uno>{{cite journal | vauthors = González-Rubio C, Ferreira-Cerdán A, Ponce IM, Arpa J, Fontán G, López-Trascasa M | title = Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation | journal = Archives of Neurology | volume = 58 | issue = 11 | pages = 1923–8 | date = Nov 2001 | pmid = 11709004 | doi=10.1001/archneur.58.11.1923}}</ref> and to low levels of [[IgG]], due to loss of iC3b and C3dg production<ref name=uno/><ref>{{cite journal | vauthors = Vyse TJ, Späth PJ, Davies KA, Morley BJ, Philippe P, Athanassiou P, Giles CM, Walport MJ | title = Hereditary complement factor I deficiency | journal = QJM | volume = 87 | issue = 7 | pages = 385–401 | date = Jul 1994 | pmid = 7922290 }}</ref><ref>{{cite journal | vauthors = Leitão MF, Vilela MM, Rutz R, Grumach AS, Condino-Neto A, Kirschfink M | title = Complement factor I deficiency in a family with recurrent infections | journal = Immunopharmacology | volume = 38 | issue = 1-2 | pages = 207–13 | date = Dec 1997 | pmid = 9476132 | doi=10.1016/s0162-3109(97)00080-5}}</ref> It has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated<ref>{{cite journal | vauthors = 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 | title = 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 | journal = Human Mutation | volume = 28 | issue = 3 | pages = 222–34 | date = Mar 2007 | pmid = 17089378 | doi = 10.1002/humu.20435 }}</ref> in development of [[Hemolytic-uremic syndrome|Haemolytic Uremic Syndrome]], a renal disease also caused by unregulated complement activation.
The factor I heavy chain has four [[Structural domain|domains]]: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) domains.<ref name="Sanchez-Gallego_2012">{{cite journal | vauthors = Sanchez-Gallego JI, Groeneveld TW, Krentz S, Nilsson SC, Villoutreix BO, Blom AM | title = Analysis of binding sites on complement factor I using artificial N-linked glycosylation | journal = The Journal of Biological Chemistry | volume = 287 | issue = 17 | pages = 13572–83 | date = April 2012 | pmid = 22393059 | pmc = 3340171 | doi = 10.1074/jbc.M111.326298 }}</ref> the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by the [[substrate (biochemistry)|substrate]] (either C3b or C4b) and a cofactor protein ([[Factor H]], C4b-binding protein, complement receptor 1, and membrane cofactor protein).<ref name="ReferenceA">{{cite journal | vauthors = Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM | title = Structural basis for complement factor I control and its disease-associated sequence polymorphisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 31 | pages = 12839–44 | date = August 2011 | pmid = 21768352 | pmc = 3150940 | doi = 10.1073/pnas.1102167108 }}</ref> Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery.<ref name="ReferenceA"/> The LDL-receptor domains contain one Calcium-binding site each.


== Synthesis ==
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.<ref name="Sanchez-Gallego_2012" />  Conventional protease inhibitors do not completely inactivate Factor I<ref>{{cite journal | vauthors = Ekdahl KN, Nilsson UR, Nilsson B | title = 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 = Journal of Immunology | volume = 144 | issue = 11 | pages = 4269–74 | date = June 1990 | pmid = 2140392 | doi =  }}</ref> 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.


The [[gene]] for Factor I in humans is located on [[chromosome 4]].<ref name="pmid2956252"/> Factor I is synthesised mostly in the liver, and is initially secreted as a single 88 kDalton gene product; this [[protein precursor|precursor protein]] is then cleaved by [[furin]] to yield the mature fI protein, which is a [[disulfide bond|disulfide-linked]] [[protein dimer|dimer]] of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton). Only the mature protein is active.
Both heavy and light chains bear [[Asparagine|Asn]]-linked [[glycans]], on three distinct [[glycosylation]] sites each.


== Structure ==
[[Crystal structure]] the crystal structure of human Factor I has been deposited as [[Protein Data Bank|PDB]]: [http://www.rcsb.org/pdb/explore/explore.do?structureId=2XRC 2XRC].


Both heavy and light chains bear [[Asparagine|Asn]]-linked [[glycans]], on three distinct [[glycosylation]] sites each.
==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 [[C3 (complement)|complement component 3]] (C3), [[Complement factor B|factor B]], [[Complement factor H|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.


The fI heavy chain has four [[Structural domain|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 (biochemistry)|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.<ref>{{cite journal | vauthors = Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM | title = Structural basis for complement factor I control and its disease-associated sequence polymorphisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 31 | pages = 12839–44 | date = Aug 2011 | pmid = 21768352 | pmc = 3150940 | doi = 10.1073/pnas.1102167108 }}</ref> The LDL-receptor domains contain one Calcium-binding site each.
'''Age-Related Macular Degeneration'''


The fI light chain is the [[serine protease]] domain containing the [[catalytic triad]] responsible for specific cleavage of C3b and C4b.
Research suggests that mutations in the CFI gene contribute to development of [[age-related macular degeneration]].<ref>{{cite journal | vauthors = Wang Q, Zhao HS, Li L | title = Association between complement factor I gene polymorphisms and the risk of age-related macular degeneration: a Meta-analysis of literature | journal = International Journal of Ophthalmology | volume = 9 | issue = 2 | pages = 298–305 | date = 2016-02-18 | pmid = 26949655 | pmc = 4761747 | doi = 10.18240/ijo.2016.02.23 }}</ref> This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.<ref>{{cite journal | vauthors = Tan PL, Garrett ME, Willer JR, Campochiaro PA, Campochiaro B, Zack DJ, Ashley-Koch AE, Katsanis N | title = Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration | journal = Investigative Ophthalmology & Visual Science | volume = 58 | issue = 3 | pages = 1570–1576 | date = March 2017 | pmid = 28282489 | pmc = 6022411 | doi = 10.1167/iovs.16-20867 }}</ref>
Conventional protease inhibitors do not completely inactivate Factor I<ref>,{{cite journal | vauthors = Ekdahl KN, Nilsson UR, Nilsson B | title = 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 = Journal of Immunology | volume = 144 | issue = 11 | pages = 4269–74 | date = Jun 1990 | pmid = 2140392 | doi = }}</ref> 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<ref>{{cite journal | vauthors = Nakamura S, Abe K | title = Genetic polymorphism of human factor I (C3b inactivator) | journal = Human Genetics | volume = 71 | issue = 1 | pages = 45–8 | year = 1985 | pmid = 3897024 | doi = 10.1007/BF00295667 }}</ref> and recently explained in terms of variants R201S, R406H, R502L.<ref>{{cite journal | vauthors = 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 | title = Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific | journal = Journal of Human Genetics | volume = 53 | issue = 11-12 | pages = 1016–21 | year = 2008 | pmid = 18825487 | doi = 10.1007/s10038-008-0337-4 }}</ref>
'''Atypical Hemolytic Uremic Syndrome'''


[[Crystal structure]] the crystal structure of human Factor I has been deposited as {{PDB|2XRC}}.
[[Atypical hemolytic uremic syndrome]] is caused by complement overactivation.<ref name="Kavanagh_2013">{{cite journal | vauthors = Kavanagh D, Goodship TH, Richards A | title = Atypical hemolytic uremic syndrome | journal = Seminars in Nephrology | volume = 33 | issue = 6 | pages = 508–30 | date = November 2013 | pmid = 24161037 | pmc = 3863953 | doi = 10.1016/j.semnephrol.2013.08.003 }}</ref>  [[Heterozygous]] mutations in the serine protease domain of the CFI gene account for 5-10% of cases.<ref name="Kavanagh_2013" />


== References ==
== References ==
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== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|33em}}
* {{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | volume = 25 | issue = 6 | pages = 683–93 | date = Jun 2011 | pmid = 21394116 | pmc = 3178140 | doi = 10.1038/eye.2011.37 }}
* {{cite journal | vauthors = Bradley DT, Zipfel PF, Hughes AE | title = Complement in age-related macular degeneration: a focus on function | journal = Eye | volume = 25 | issue = 6 | pages = 683–93 | date = June 2011 | pmid = 21394116 | pmc = 3178140 | doi = 10.1038/eye.2011.37 }}
* {{cite journal | vauthors = Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD | title = Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient | journal = American Journal of Kidney Diseases | volume = 53 | issue = 2 | pages = 321–6 | date = Feb 2009 | pmid = 18805611 | pmc = 2879708 | doi = 10.1053/j.ajkd.2008.06.027 }}
* {{cite journal | vauthors = Chan MR, Thomas CP, Torrealba JR, Djamali A, Fernandez LA, Nishimura CJ, Smith RJ, Samaniego MD | title = Recurrent atypical hemolytic uremic syndrome associated with factor I mutation in a living related renal transplant recipient | journal = American Journal of Kidney Diseases | volume = 53 | issue = 2 | pages = 321–6 | date = February 2009 | pmid = 18805611 | pmc = 2879708 | doi = 10.1053/j.ajkd.2008.06.027 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = Human Molecular Genetics | volume = 19 | issue = 12 | pages = 2497–506 | date = Jun 2010 | pmid = 20332099 | pmc = 2876884 | doi = 10.1093/hmg/ddq112 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = Human Molecular Genetics | volume = 19 | issue = 12 | pages = 2497–506 | date = June 2010 | pmid = 20332099 | pmc = 2876884 | doi = 10.1093/hmg/ddq112 }}
* {{cite journal | vauthors = Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM | title = Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I | journal = European Journal of Immunology | volume = 40 | issue = 1 | pages = 172–85 | date = Jan 2010 | pmid = 19877009 | doi = 10.1002/eji.200939280 }}
* {{cite journal | vauthors = Nilsson SC, Kalchishkova N, Trouw LA, Fremeaux-Bacchi V, Villoutreix BO, Blom AM | title = Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I | journal = European Journal of Immunology | volume = 40 | issue = 1 | pages = 172–85 | date = January 2010 | pmid = 19877009 | doi = 10.1002/eji.200939280 }}
* {{cite journal | vauthors = Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR | title = Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score | journal = Molecular Medicine | volume = 16 | issue = 7-8 | pages = 247–53 | year = 2010 | pmid = 20379614 | pmc = 2896464 | doi = 10.2119/molmed.2009.00159 }}
* {{cite journal | vauthors = Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR | title = Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score | journal = Molecular Medicine | volume = 16 | issue = 7–8 | pages = 247–53 | year = 2010 | pmid = 20379614 | pmc = 2896464 | doi = 10.2119/molmed.2009.00159 }}
* {{cite journal | vauthors = 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 | title = Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome | journal = Annals of Human Genetics | volume = 74 | issue = 1 | pages = 17–26 | date = Jan 2010 | pmid = 20059470 | doi = 10.1111/j.1469-1809.2009.00554.x }}
* {{cite journal | vauthors = 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 | title = Epidemiological approach to identifying genetic predispositions for atypical hemolytic uremic syndrome | journal = Annals of Human Genetics | volume = 74 | issue = 1 | pages = 17–26 | date = January 2010 | pmid = 20059470 | doi = 10.1111/j.1469-1809.2009.00554.x }}
* {{cite journal | vauthors = 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 | title = Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS) | journal = Nephrology, Dialysis, Transplantation | volume = 25 | issue = 7 | pages = 2195–202 | date = Jul 2010 | pmid = 20106822 | doi = 10.1093/ndt/gfq010 }}
* {{cite journal | vauthors = 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 | title = Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS) | journal = Nephrology, Dialysis, Transplantation | volume = 25 | issue = 7 | pages = 2195–202 | date = July 2010 | pmid = 20106822 | doi = 10.1093/ndt/gfq010 }}
* {{cite journal | vauthors = 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 | title = Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome | journal = Kidney International | volume = 77 | issue = 4 | pages = 339–49 | date = Feb 2010 | pmid = 20016463 | doi = 10.1038/ki.2009.472 }}
* {{cite journal | vauthors = 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 | title = Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome | journal = Kidney International | volume = 77 | issue = 4 | pages = 339–49 | date = February 2010 | pmid = 20016463 | doi = 10.1038/ki.2009.472 }}
* {{cite journal | vauthors = Kondo N, Bessho H, Honda S, Negi A | title = Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration | journal = European Journal of Human Genetics | volume = 18 | issue = 6 | pages = 634–5 | date = Jun 2010 | pmid = 20087399 | pmc = 2987347 | doi = 10.1038/ejhg.2009.243 }}
* {{cite journal | vauthors = Kondo N, Bessho H, Honda S, Negi A | title = Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration | journal = European Journal of Human Genetics | volume = 18 | issue = 6 | pages = 634–5 | date = June 2010 | pmid = 20087399 | pmc = 2987347 | doi = 10.1038/ejhg.2009.243 }}
* {{cite journal | vauthors = Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ | title = Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome | journal = Human Mutation | volume = 31 | issue = 6 | pages = E1445-60 | date = Jun 2010 | pmid = 20513133 | doi = 10.1002/humu.21256 }}
* {{cite journal | vauthors = Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ | title = Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome | journal = Human Mutation | volume = 31 | issue = 6 | pages = E1445–60 | date = June 2010 | pmid = 20513133 | doi = 10.1002/humu.21256 }}
* {{cite journal | vauthors = Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM | title = Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes | journal = Investigative Ophthalmology & Visual Science | volume = 50 | issue = 12 | pages = 5818–27 | date = Dec 2009 | pmid = 19661236 | pmc = 2826794 | doi = 10.1167/iovs.09-3928 }}
* {{cite journal | vauthors = Reynolds R, Hartnett ME, Atkinson JP, Giclas PC, Rosner B, Seddon JM | title = Plasma complement components and activation fragments: associations with age-related macular degeneration genotypes and phenotypes | journal = Investigative Ophthalmology & Visual Science | volume = 50 | issue = 12 | pages = 5818–27 | date = December 2009 | pmid = 19661236 | pmc = 2826794 | doi = 10.1167/iovs.09-3928 }}
* {{cite journal | vauthors = Shin DH, Webb BM, Nakao M, Smith SL | title = Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence | journal = Molecular Immunology | volume = 46 | issue = 11-12 | pages = 2299–308 | date = Jul 2009 | pmid = 19423168 | pmc = 2699631 | doi = 10.1016/j.molimm.2009.04.002 }}
* {{cite journal | vauthors = Shin DH, Webb BM, Nakao M, Smith SL | title = Characterization of shark complement factor I gene(s): genomic analysis of a novel shark-specific sequence | journal = Molecular Immunology | volume = 46 | issue = 11–12 | pages = 2299–308 | date = July 2009 | pmid = 19423168 | pmc = 2699631 | doi = 10.1016/j.molimm.2009.04.002 }}
* {{cite journal | vauthors = Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, Marquart H, Muller K, Sjöholm AG, Truedsson L, Villoutreix BO, Blom AM | title = Genetic, molecular and functional analyses of complement factor I deficiency | journal = European Journal of Immunology | volume = 39 | issue = 1 | pages = 310–23 | date = Jan 2009 | pmid = 19065647 | doi = 10.1002/eji.200838702 }}
* {{cite journal | vauthors = Nilsson SC, Trouw LA, Renault N, Miteva MA, Genel F, Zelazko M, Marquart H, Muller K, Sjöholm AG, Truedsson L, Villoutreix BO, Blom AM | title = Genetic, molecular and functional analyses of complement factor I deficiency | journal = European Journal of Immunology | volume = 39 | issue = 1 | pages = 310–23 | date = January 2009 | pmid = 19065647 | doi = 10.1002/eji.200838702 }}
* {{cite journal | vauthors = Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM | title = Variation near complement factor I is associated with risk of advanced AMD | journal = European Journal of Human Genetics | volume = 17 | issue = 1 | pages = 100–4 | date = Jan 2009 | pmid = 18685559 | pmc = 2985963 | doi = 10.1038/ejhg.2008.140 }}
* {{cite journal | vauthors = Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM | title = Variation near complement factor I is associated with risk of advanced AMD | journal = European Journal of Human Genetics | volume = 17 | issue = 1 | pages = 100–4 | date = January 2009 | pmid = 18685559 | pmc = 2985963 | doi = 10.1038/ejhg.2008.140 }}
* {{cite journal | vauthors = Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J | title = A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles | journal = International Journal of Legal Medicine | volume = 125 | issue = 1 | pages = 121–5 | date = Jan 2011 | pmid = 19693526 | doi = 10.1007/s00414-009-0369-0 }}
* {{cite journal | vauthors = Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J | title = A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles | journal = International Journal of Legal Medicine | volume = 125 | issue = 1 | pages = 121–5 | date = January 2011 | pmid = 19693526 | doi = 10.1007/s00414-009-0369-0 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = Blood | volume = 115 | issue = 2 | pages = 379–87 | date = Jan 2010 | pmid = 19861685 | pmc = 2829859 | doi = 10.1182/blood-2009-05-221549 }}
* {{cite journal | vauthors = 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 | title = 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 | journal = Blood | volume = 115 | issue = 2 | pages = 379–87 | date = January 2010 | pmid = 19861685 | pmc = 2829859 | doi = 10.1182/blood-2009-05-221549 }}
* {{cite journal | vauthors = Li MZ, Yu DM, Yu P, Liu DM, Wang K, Tang XZ | title = Mitochondrial gene mutations and type 2 diabetes in Chinese families | journal = Chinese Medical Journal | volume = 121 | issue = 8 | pages = 682–6 | date = Apr 2008 | pmid = 18701018 | doi =  }}
* {{cite journal | vauthors = Li MZ, Yu DM, Yu P, Liu DM, Wang K, Tang XZ | title = Mitochondrial gene mutations and type 2 diabetes in Chinese families | journal = Chinese Medical Journal | volume = 121 | issue = 8 | pages = 682–6 | date = April 2008 | pmid = 18701018 | doi =  }}
* {{cite journal | vauthors = Nilsson SC, Nita I, Månsson L, Groeneveld TW, Trouw LA, Villoutreix BO, Blom AM | title = Analysis of binding sites on complement factor I that are required for its activity | journal = The Journal of Biological Chemistry | volume = 285 | issue = 9 | pages = 6235–45 | date = Feb 2010 | pmid = 20044478 | pmc = 2825419 | doi = 10.1074/jbc.M109.097212 }}
* {{cite journal | vauthors = Nilsson SC, Nita I, Månsson L, Groeneveld TW, Trouw LA, Villoutreix BO, Blom AM | title = Analysis of binding sites on complement factor I that are required for its activity | journal = The Journal of Biological Chemistry | volume = 285 | issue = 9 | pages = 6235–45 | date = February 2010 | pmid = 20044478 | pmc = 2825419 | doi = 10.1074/jbc.M109.097212 }}
{{refend}}
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Latest revision as of 11:59, 10 January 2019

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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.[11] 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.[16]

References

  1. ↑ Nelson RA, Jensen J, Gigli I, Tamura N (March 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.
  2. ↑ Lachmann PJ, Müller-Eberhard HJ (April 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.
  3. ↑ Nilsson SC, Sim RB, Lea SM, Fremeaux-Bacchi V, Blom AM (August 2011). "Complement factor I in health and disease". Molecular Immunology (Submitted manuscript). 48 (14): 1611–20. doi:10.1016/j.molimm.2011.04.004. PMID 21529951.
  4. ↑ 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". The Journal of Biological Chemistry. 262 (21): 10065–71. PMID 2956252.
  5. ↑ Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster AD, Walport MJ (February 1996). "The molecular basis of hereditary complement factor I deficiency". The Journal of Clinical Investigation. 97 (4): 925–33. doi:10.1172/JCI118515. PMC 507137. PMID 8613545.
  6. ↑ Julen N, Dauchel H, Lemercier C, Sim RB, Fontaine M, Ripoche J (January 1992). "In vitro biosynthesis of complement factor I by human endothelial cells". European Journal of Immunology. 22 (1): 213–7. doi:10.1002/eji.1830220131. PMID 1530917.
  7. ↑ Whaley K (March 1980). "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. doi:10.1084/jem.151.3.501. PMC 2185797. PMID 6444659.
  8. ↑ Tsiftsoglou SA, Arnold JN, Roversi P, Crispin MD, Radcliffe C, Lea SM, Dwek RA, Rudd PM, Sim RB (November 2006). "Human complement factor I glycosylation: structural and functional characterisation of the N-linked oligosaccharides". Biochimica et Biophysica Acta. 1764 (11): 1757–66. CiteSeerX 10.1.1.712.1764. doi:10.1016/j.bbapap.2006.09.007. PMID 17055788.
  9. ↑ "FURIN furin, paired basic amino acid cleaving enzyme [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-30.
  10. ↑ "CFI complement factor I [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-03-27.
  11. ↑ 11.0 11.1 Sanchez-Gallego JI, Groeneveld TW, Krentz S, Nilsson SC, Villoutreix BO, Blom AM (April 2012). "Analysis of binding sites on complement factor I using artificial N-linked glycosylation". The Journal of Biological Chemistry. 287 (17): 13572–83. doi:10.1074/jbc.M111.326298. PMC 3340171. PMID 22393059.
  12. ↑ 12.0 12.1 Roversi P, Johnson S, Caesar JJ, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SM (August 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.
  13. ↑ Ekdahl KN, Nilsson UR, Nilsson B (June 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.
  14. ↑ Wang Q, Zhao HS, Li L (2016-02-18). "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. doi:10.18240/ijo.2016.02.23. PMC 4761747. PMID 26949655.
  15. ↑ Tan PL, Garrett ME, Willer JR, Campochiaro PA, Campochiaro B, Zack DJ, Ashley-Koch AE, Katsanis N (March 2017). "Systematic Functional Testing of Rare Variants: Contributions of CFI to Age-Related Macular Degeneration". Investigative Ophthalmology & Visual Science. 58 (3): 1570–1576. doi:10.1167/iovs.16-20867. PMC 6022411. PMID 28282489.
  16. ↑ 16.0 16.1 Kavanagh D, Goodship TH, Richards A (November 2013). "Atypical hemolytic uremic syndrome". Seminars in Nephrology. 33 (6): 508–30. doi:10.1016/j.semnephrol.2013.08.003. PMC 3863953. PMID 24161037.

Further reading

External links

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