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Complement Factor I
Identifiers
Symbol CFI
Alt. symbols C3b-INA, FI, IF, KAF, factor I
Entrez 3426
HUGO 5394
OMIM 217030
RefSeq NM_000204
UniProt P05156
Other data
EC number 3.4.21.45
Locus Chr. 4 q25

Complement Factor I (fI) 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]

Contents

Pathology

Factor I deficiency in turn leads to low levels of complement component 3 (C3) in plasma, due to unregulated activation of the complement alternative pathway, and it has been associated with recurrent bacterial infections in children; more recently, mutations in the Factor I gene have been shown to be implicated[3] 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.[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

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 precise biological function of the heavy chain is not known, but it is likely to play a key role in recognising the fI cleavage substrates (C3b and C4b) and the cofactor proteins needed for cleavage of C3b (Factor H, CR1, MCP) and C4b (C4BP). The LDL-receptor domains are likely to 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[5] but they can do so if the enzyme is pre-incubated with its substrate: this suggests either an induced-fit rearrangement of the active site, or a more general rearrangement of the whole molecule.

Genetic polymorphism in Factor I has been observed[6] and recently explained in terms of variants R201S, R406H, R502L.[7]

References

  1. ^ Nelson R, Jensen J, Gigli I, Tamura N (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 P, Müller-Eberhard H (1968). "The demonstration in human serum of "conglutinogen-activating factor" and its effect on the third component of complement". J Immunol 100 (4): 691–8. PMID 5645214.  
  3. ^ Saunders R, Abarrategui-Garrido C, Frémeaux-Bacchi V, Goicoechea de Jorge E, Goodship T, López Trascasa M, Noris M, Ponce Castro I, Remuzzi G, Rodríguez de Córdoba S, Sánchez-Corral P, Skerka C, Zipfel P, Perkins S (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". Hum Mutat 28 (3): 222–34. doi:10.1002/humu.20435. PMID 17089378.  
  4. ^ Goldberger G, Bruns G, Rits M, Edge M, Kwiatkowski D (1987). "Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4.". J Biol Chem 262 (21): 10065–71. PMID 2956252.  
  5. ^ ,Ekdahl KN, Nilsson UR, Nilsson B. (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.". J. Immunology 144 (11): 4269–74. PMID 2140392.  
  6. ^ Nakamura S, Abe K (1985). "Genetic polymorphism of human factor I (C3b inactivator)". Hum Genet 71 (1): 45–8. doi:10.1007/BF00295667. PMID 3897024.  
  7. ^ Yuasa I et al. (2008). "Molecular basis of complement factor I (CFI) polymorphism: one of two polymorphic suballeles responsible for CFI A is Japanese-specific.". J. Hum Genet 53 (11-12): 1016–21. doi:10.1007/s10038-008-0337-4. PMID 18825487.  
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