Complement control protein
Encyclopedia
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.
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.
Other soluble complement regulators that do not belong to the RCA/CCP family are Complement Factor I
and C1 inhibitor.
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.
residues each of that has 4 conserved cysteine
s, arranged in two conserved disulfide bonds (oxidized in 'abab' manner), and one also 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)).
. Transgenic pigs that express complement regulation factors may one day be useful for xenotransplantation
.
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
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
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
complexes.
Most of the complement control proteins act on the convertases, C3b
C3b
C3b is the larger of two elements formed by the cleavage of complement component 3. C3b covalently bonds to microbial cell surfaces within an organism's body. This leads to the production of surface-bound C3 convertase and thus more C3b components. Bound C3b also aids in opsonization of the microbe...
.Bb and C4b.2a, which are bimolecular complexes formed early on in the complement cascade.
Members
The best-studied members of this family are:- Complement receptor 1 (CR1 or CD35)
- Membrane cofactor protein (MCP or CD46CD46CD46 complement regulatory protein also known as CD46 and Membrane Cofactor Protein is a protein which in humans is encoded by the CD46 gene. CD46 is an inhibitory complement receptor.- Gene :...
) - C4b-binding protein (C4BP).
- Decay-accelerating factor (DAF or CD55)
- Factor HFactor HFactor H is a member of the regulators of complement activation family and is a complement control protein. It is a large , soluble glycoprotein that circulates in human plasma...
(fH)
Other soluble complement regulators that do not belong to the RCA/CCP family are Complement Factor I
Complement factor I
Complement factor I, also known as C3B/C4B inactivator, is a protein that in humans is encoded by the CFI gene.Complement Factor I is a protein of the complement system, first isolated in 1966 in guinea pig serum that regulates complement activation by cleaving cell-bound or fluid phase C3b and...
and C1 inhibitor.
Mechanisms of protection
Every cellCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
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
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic 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
RCA proteins typically formed by CCP domains, also termed Sushi domains or Short Consensus Repeats (SCR). Such beta-sandwich domains contain about 60 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues each of that has 4 conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s, arranged in two conserved disulfide bonds (oxidized in 'abab' manner), and one also conserved tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
, 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
NMR
NMR may refer to:Applications of Nuclear Magnetic Resonance:* Nuclear magnetic resonance* NMR spectroscopy* Solid-state nuclear magnetic resonance* Protein nuclear magnetic resonance spectroscopy* Proton NMR* Carbon-13 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)).
Clinical significance
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 degenerationMacular degeneration
Age-related macular degeneration is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults...
. Transgenic pigs that express complement regulation factors may one day be useful for xenotransplantation
Xenotransplantation
Xenotransplantation , is the transplantation of living cells, tissues or organs from one species to another. Such cells, tissues or organs are called xenografts or xenotransplants...
.