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Complement Factor I

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Title: Complement Factor I  
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Subject: Chromosome 4 (human), Complement control protein
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Complement Factor I

Complement factor I
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PDB Ortholog search: RCSB

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]


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.


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.


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]



Further reading

External links

  • GeneReviews/NCBI/NIH/UW entry on Atypical Hemolytic-Uremic Syndrome
  • OMIM entries on Atypical Hemolytic-Uremic Syndrome
  • The S01.199
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