Complement factor I

Complement factor I, also known as C3b/C4b inactivator, is a is_associated_with::protein that in humans is encoded by the CFI is_associated_with::gene.

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

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 in development of Haemolytic Uremic Syndrome, a renal disease also caused by unregulated complement activation.

Synthesis
The is_associated_with::gene for Factor I in humans is located on is_associated_with::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 is_associated_with::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 is_associated_with::glycans, on three distinct is_associated_with::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 (is_associated_with::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. The LDL-receptor domains contain one Calcium-binding site each.

The fI light chain is the is_associated_with::serine protease domain containing the is_associated_with::catalytic triad responsible for specific cleavage of C3b and C4b. Conventional protease inhibitors do not completely inactivate Factor I 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.

is_associated_with::Genetic polymorphism in Factor I has been observed and recently explained in terms of variants R201S, R406H, R502L.

is_associated_with::Crystal structure the crystal structure of human Factor I has been deposited as.