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Complement factor I, also known as C3b/C4b inactivator, is a protein that in humans is encoded by the CFI gene. Complement factor I (factor I) 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. It is a soluble glycoprotein that circulates in human blood at an average concentration of 35 μg/mL.

Synthesis
The gene for Factor I in humans is located on chromosome 4. Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, kerationcytes, and endothelial cells. When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions. Then, factor I is cleaved by furin to yield the mature factor I 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
Factor I is a glycoprotein heterodimer consisting of a disulfide linked heavy chain and light chain.

The factor I heavy chain has four domains: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) 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, C4b-binding protein, complement receptor 1, and membrane cofactor protein). 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 factor I light chain contains only the serine protease domain. This domain contains the catalytic triad His-362, Asp-411, and Ser-507, which is 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.

Both heavy and light chains bear Asn-linked glycans, on three distinct glycosylation sites each.

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

Clinical Significance
There are several clinical implications of dysregulated factor I activity. Mutations in the Complement Factor I gene can lead to low levels of factor I and may result in increased complement activity. Factor I deficiency in turn leads to low levels of complement component 3 (C3), factor B, factor H and properdin. in plasma, due to unregulated activation of C3 convertase, and to low levels of IgG, due to loss of iC3b and C3dg production. In addition to the following diseases, low factor I is associated with recurrent bacterial infections in children.

Age-Related Macular Degeneration

Research suggests that several mutations in the CFI gene contribute to development of age-related macular degeneration. This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.

Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome is caused by complement overactivation. Heterozygous mutations in the serine protease domain of the CFI gene account for 5-10% of cases.