Complement control protein

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The complement system has the potential to cause damage to host tissue. Indeed, the symptoms of many diseases arise from disproportionate or misdirected complement-mediated effects. In the healthy human, complement activation is tightly regulated and directed towards foreign particles (such as viruses and bacteria) or unwanted material (such as cell debris and antibody-antigen complexes). Regulation is mediated by a range of specialised cell-surface and soluble proteins. Most of the regulators act at the level of the convertases (such as C3b.Bb and C4b.2a), which are the bimolecular complexes formed early on in the activation cascade. These homologous proteins belong to a family called the "regulators of complement activation (RAC)" or "complement control proteins (CCP)".

1 Structure
2 Members
3 Role in protection
4 Clinical significance
5 Sources
6 External links

[edit] Structure

CCP domains , also called Sushi or Short Consesus 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.

[edit] Members

The best studied members of this family are:

complement receptor 1 (CR1 or CD35)
decay-accelerating factor (DAF or CD55)
membrane cofactor protein (MCP or CD46)
factor H (fH)
C4b-binding protein (C4BP).

Other soluble complement regulators, not belonging to the RCA/CCP family are Complement Factor I and C1 inhibitor.

[edit] Role in 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.

[edit] 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.

[edit] 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:10.1034/j.1600-065X.2001.1800113.x. PMID 11414356.