Complement control protein
The complement system distinguishes "self" from "non-self" via a range of specialized cell-surface and soluble proteins. These homologous proteins belong to a family called the "regulators of complement activation (RCA)" or "complement control proteins (CCP)". Complement control proteins work in concert to regulate the system and keep it from damaging host tissue while simultaneously directing it towards foreign particles such as viruses and bacteria, and unwanted material such as cell debris and antibody-antigen complexes.
The best-studied members of this family are:
- Complement receptor 1 (CR1 or CD35)
- Membrane cofactor protein (MCP or CD46)
- C4b-binding protein (C4BP).
- Decay-accelerating factor (DAF or CD55)
- Factor H (fH)
Mechanisms of protection
Every cell in the human body is protected by one or more of the membrane-associated RCA proteins, CR1, DAF or MCP. Factor H and C4BP circulate in the plasma and are recruited to self-surfaces through binding to host-specific polysaccharides such as the glycosaminoglycans. All act to disrupt the formation of the convertases or to shorten the life-span of any complexes that do manage to form. Their presence on self-surfaces, and their absence from the surfaces of foreign particles, means that these regulators perform the important task of targeting complement to where it is needed - on the invading bacterium for example - while preventing activation on host tissues.
For example, C3b.Bb is an important convertase that is part of the alternative pathway, and it is formed when factor B binds C3b and is subsequently cleaved. To prevent this from happening, factor H competes with factor B to bind C3b; if it manages to bind, then the convertase is not formed. Factor H can bind C3b much more easily in the presence of sialic acid, which is a component of most cells in the human body; conversely, in the absence of sialic acid, factor B can bind C3b more easily. This means that if C3b is bound to a "self" cell, the presence of sialic acid and the binding of factor H will prevent the complement cascade from activating; if C3b is bound to a bacterium, factor B will bind and the cascade will be set off as normal.
RCA proteins typically possess CCP domains, also termed Sushi domains or Short Consensus Repeats (SCR). Such beta-sandwich domains contain about 60 amino acid residues, each with 4 conserved cysteines arranged in two conserved disulfide bonds (oxidized in 'abab' manner), and a conserved tryptophan, but otherwise can vary greatly in sequence.
The first CCP structure determined was a solution structure of the 16th module of factor H (pdb:1hcc). Since then, other CCP domains have been solved either by NMR-spectroscopy (also relaxation studies, e.g. module 2 and 3 from CD55 (pdb:1nwv)) or by X-ray diffraction (also with co-crystallized partner, e.g. CR2 CCP modules complexed with C3d (pdb:1ghq)).
The importance of complement regulation for good health is highlighted by recent work that seems to imply that individuals carrying point mutations or single nucleotide polymorphisms in their genes for factor H may be more susceptible to diseases including atypical hemolytic uremic syndrome, dense deposit diseases (or membranoproliferative glomrulonephritis type 2) and - most notably because of its prevalence in the elderly - age-related macular degeneration. Transgenic pigs that express complement regulation factors may one day be useful for xenotransplantation.
Complement control proteins also play a role in malignancy. Complement proteins protect against malignant cells- both by direct complement attack and through initiation of Complement-dependent cytotoxicity, which synergises with specific monoclonal antibody therapies. However, some malignant cells have been shown to have increased expression of membrane-bound complement control proteins, especially CD46, DAF and CD59. This mechanism allows some tumours to evade complement action.
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