Complement component C1 inhibitor (C1INH) is a single-chain, 105-kDa plasma glycoprotein with 478 amino acid residues. Carbohydrate side-chains constitute up to a third of the weight, making C1INH one of the most highly glycosylated plasma proteins. C1INH is synthesized mainly in the liver, but also by monocytes and skin fibroblasts. The synthesis is stimulated by interferon γ, interleukin 1 (IL-1) and IL-6. The gene encoding C1INH is located in chromosome 11 and consists of eight exons and seven introns. The gene contains an unusually high number of Alu repeats. These repeats predispose the gene region to rearrangements by homologous recombination, which may lead to unequal crossing-over and deletions and insertions in the C1INH gene.
Complement C1 inhibitor (C1INH) belongs to the family of serine protease inhibitors (serpins). The serpins (e.g. antithrombin III, α1-antitrypsin and α2-macroglobulin) share structural and functional properties. The target specificity is determined by the structure of the serpin’s reactive centre which binds to the target protease. Although the serpin is cleaved by the protease, it remains tightly bound, thereby rendering the protease inactive.
In the complement system, complement C1 inhibitor (C1INH) inhibits the C1r and C1s serine proteases and prevents the autoactivation of the C1qrs complex. In circulation, C1INH is bound reversibly to C1s and C1r. When C1q is activated, C1r and C1s cleave C1INH and remain bound, as described above. C1 inhibitor (C1INH) is also a biologically significant inhibitor of kallikrein and coagulation factor XII. In addition, C1INH has been shown to inhibit plasmin and coagulation factor XIa, but these functions are of less importance. Recent studies indicate that C1INH can also inhibit the MBL-associated serine proteases MASP-1 and MASP-2.
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