Complement factor I

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CFI
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CFI, AHUS3, ARMD13, C3BINA, C3b-INA, FI, IF, KAF, complement factor I
External IDs MGI: 105937 HomoloGene: 171 GeneCards: 3426
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000204
NM_001318057

NM_007686

RefSeq (protein)

NP_000195.2
NP_001304986.1

NP_031712.2

Location (UCSC) Chr 4: 109.74 – 109.8 Mb Chr 3: 129.84 – 129.88 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene.[3][4]

Complement Factor I (fI) is a protein of the complement system, first isolated in 1966 in guinea pig serum,[5] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.[6]

Pathology[edit]

Factor I deficiency in turn leads to low levels of complement component 3 (C3), factor B, factor H and properdin.[7] in plasma, due to unregulated activation of C3 convertase,[8] and to low levels of IgG, due to loss of iC3b and C3dg production[8][9][10] It has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated[11] in development of Haemolytic Uremic Syndrome, a renal disease also caused by unregulated complement activation.

Synthesis[edit]

The gene for Factor I in humans is located on chromosome 4.[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-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[edit]

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.[12] 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[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.

Genetic polymorphism in Factor I has been observed[14] and recently explained in terms of variants R201S, R406H, R502L.[15]

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

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ "Entrez Gene: complement factor I". 
  4. ^ a b 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. PMC 1809586free to read. PMID 16412054. 
  8. ^ a b 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. doi:10.1001/archneur.58.11.1923. PMID 11709004. 
  9. ^ 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. 
  10. ^ 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. PMID 9476132. 
  11. ^ 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. 
  12. ^ 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 3150940free to read. PMID 21768352. 
  13. ^ ,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. 
  14. ^ 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. 
  15. ^ 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[edit]

External links[edit]