Complement Factor I
(fI) is a protein
of the Complement system
, first isolated in 1966 in guinea pig serum
that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.
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 in development of Haemolytic Uremic Syndrome
, a renal disease also caused by unregulated complement activation.
for Factor I in humans is located on chromosome 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.
Both heavy and light chains bear Asn
, on three distinct glycosylation
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.
Genetic polymorphism in Factor I has been observed.