Complement factor I

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Complement factor I
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CFI ; AHUS3; C3BINA; C3b-INA; FI; IF; KAF
External IDs OMIM217030 MGI105937 HomoloGene171 GeneCards: CFI Gene
EC number 3.4.21.45
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 [1] [2]

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[edit]

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[5] 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.[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[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.[6] 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[7] 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[8] and recently explained in terms of variants R201S, R406H, R502L.[9]

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

References[edit]

  1. ^ "Entrez Gene: complement factor I". 
  2. ^ a b 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". J. Biol. Chem. 262 (21): 10065–71. PMID 2956252. 
  3. ^ 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. 
  4. ^ Lachmann P, Müller-Eberhard H (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. ^ 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. 
  6. ^ Roversi P, Johnson S, Caesar JJE, McLean F, Leath KJ, Tsiftsoglou SA, Morgan BP, Harris CL, Sim RB, Lea SML (2011). "Structural basis for complement factor I control and its disease-associated sequence polymorphisms)". PNAS 108 (31): 12839–12844. doi:10.1073/pnas.1102167108. PMC 3150940. PMID 21768352. 
  7. ^ ,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". Journal of Immunologyogy 144 (11): 4269–74. PMID 2140392. 
  8. ^ 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. 
  9. ^ 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". Journal of Human Genetics 53 (11–12): 1016–21. doi:10.1007/s10038-008-0337-4. PMID 18825487. 

Further reading[edit]

External links[edit]