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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 (RAC)" 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.
Most of the complement control proteins act on the convertases, C3b.Bb and C4b.2a, which are bimolecular complexes formed early on in the complement cascade.
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Members
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)
Other soluble complement regulators that do not belong to the RCA/CCP family are Complement Factor I and C1 inhibitor.
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.
Structure
CCP domains , also called Sushi or Short Consensus Repeat(SCR) domains, contain consecutive domains of about 60 residues eachthat have 4 conserved cysteines, arranged in two conserved disulfide bonds, and one conserved tryptophan, but otherwise can vary greatly in sequence.
Clinical significance
The importance of complement regulation for good health is highlighted by recent work that seems to imply that individuals who carry point mutations or single nucleotide polymorphisms in their genes for factor H may be more susceptible to diseases including atypical hemolytic uremic syndrome,[1] dense deposit diseases (or membranoproliferative glomrulonephritis type 2) and - most notably because of its prevalence in the elderly - age-related macular degeneration. [2] Transgenic pigs that express complement regulation factors may one day be useful for xenotransplantation.
Sources
- ^ Buddles, M.R., Donne, R.L., Richards, A., Goodship, J. & Goodship, T.H. Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uremic syndrome. Am J Hum Genet 66, 1721-2 (2000).
- ^ Hageman, G.S. et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102, 7227-32 (2005).
- Kirkitadze M, Barlow P (2001). "Structure and flexibility of the multiple domain proteins that regulate complement activation". Immunol Rev 180: 146–61. doi:. PMID 11414356.
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