Complement factor I, also known asC3b/C4b inactivator, is aprotein that in humans is encoded by theCFIgene. Complement factor I (factor I) is a protein of thecomplement system, first isolated in 1966 inguinea pigserum,[5] that regulates complement activation by cleaving cell-bound or fluid phase C3b and C4b.[6] It is a solubleglycoprotein that circulates in human blood at an average concentration of 35 μg/mL.[7]
Thegene for Factor I in humans is located onchromosome 4.[8] Factor I is synthesized mostly in the liver, but also in monocytes, fibroblasts, keratinocytes, and endothelial cells.[9][10][11] When synthesized, it is a 66kDa polypeptide chain with N-linked glycans at 6 positions.[12] Then, factor I is cleaved byfurin to yield the mature factor I protein, which is adisulfide-linkeddimer of heavy chain (residues 19-335, 51 kDalton) and light chain (residues 340-583, 37 kDalton).[13] Only the mature protein is active.
Factor I is a glycoproteinheterodimer consisting of a disulfide linked heavy chain and light chain.[14]
The factor I heavy chain has fourdomains: an FI membrane attack complex (FIMAC) domain, CD5 domain, and low density lipoprotein receptor 1 and 2 (LDLr1 and LDLr2) domains.[15] the heavy chain plays an inhibitory role in maintaining the enzyme inactive until it meets the complex formed by thesubstrate (either C3b or C4b) and a cofactor protein (Factor H, C4b-binding protein, complement receptor 1, and membrane cofactor protein).[16] Upon binding of the enzyme to the substrate:cofactor complex, the heavy:light chain interface is disrupted, and the enzyme activated by allostery.[16] The LDL-receptor domains contain one Calcium-binding site each.
The factor I light chain contains only theserine protease domain. This domain contains thecatalytic triad His-362, Asp-411, and Ser-507, which is responsible for specific cleavage of C3b and C4b.[15] Conventional protease inhibitors do not completely inactivate Factor I[17] 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 bearAsn-linkedglycans, on three distinctglycosylation sites each.
Dysregulated factor I activity has clinical implications. Loss of function mutations in the Complement Factor I gene lead to low levels of factor I which results in increased complement activity. Factor I deficiency in turn leads to low levels ofcomplement component 3 (C3),factor B,factor H andproperdin in blood, due to unregulated activation ofC3 convertase, and to low levels ofIgG, due to loss ofiC3b and C3dg production. In addition to the following diseases, low factor I is associated with recurrent bacterial infections in children.
Research suggests that mutations in the CFI gene contribute to development ofage-related macular degeneration.[18] This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye.[19]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Nelson RA, Jensen J, Gigli I, Tamura N (March 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.PMID5960883.
^Julen N, Dauchel H, Lemercier C, Sim RB, Fontaine M, Ripoche J (January 1992). "In vitro biosynthesis of complement factor I by human endothelial cells".European Journal of Immunology.22 (1):213–7.doi:10.1002/eji.1830220131.PMID1530917.S2CID30130789.
Yuasa I, Irizawa Y, Nishimukai H, Fukumori Y, Umetsu K, Nakayashiki N, Saitou N, Henke L, Henke J (January 2011). "A hypervariable STR polymorphism in the complement factor I (CFI) gene: Asian-specific alleles".International Journal of Legal Medicine.125 (1):121–5.doi:10.1007/s00414-009-0369-0.PMID19693526.S2CID37565572.
