Overview of Complement System
The complement system plays an important role in the cellular integrity and
tissue homeostasis. For example, the activated complement system can mediate the removal of microorganisms and the
clearance of modified cells self, such as apoptotic cells. The pathways of complement activation are three methods
and can be divided into four main steps: initiation of complement activation, C3 convertase activation and
amplification, C5 convertase activation, and terminal pathway activity or the assembly of the terminal complement
complex (TCC; also known as membrane attack complex MAC), shown in Fig.1.
Which are Complement Regulators?
Complement regulators control the spontaneously activated complement cascade. At the same time, any disturbances in
this delicate balance can cause damage to tissues and autoimmune disease. Table 1 is listed seven complement
regulators. In the table, MCP refers to the memebrane cofactor protein and DAF means the decay accelerating factor.
C1 INH means C1 inhibitor. GPI is glycosylphosphatidylinositol.
Table.1 Seven complement regulators.
|
Regulator
|
Alternative name
|
Point of action
|
Cell surface binding or expression
|
|
RCA/CCP family
|
CD55
|
DAF
|
C3
|
GPI anchor expression via most cell types, including erythrocytes, epithelial cells and
endothelial cells
|
|
Factor H
|
None
|
Alternative pathway
|
Acquired to surface
|
|
CD46
|
MCP
|
C3
|
All cells except erythrocytes
|
|
Others
|
C1INH
|
None
|
Classical pathway and lectin
pathway
|
NA
|
|
CD59
|
Protectin
|
TCC
|
GPI anchor expression via erythrocytes and most nucleated cells, including renal cells
|
|
Vitronectin
|
S-protein
|
Terminal pathway
|
NA
|
|
Clusterin
|
SP-40,40 and apolipoprotein J
|
Terminal pathway
|
NA
|
Structure of Complement Regulators
-
CD55 (also called DAF) is a 70 kDa glycoprotein that is present on the membranes of peripheral blood cells,
vascular endothelial cells, placenta and many kinds of epithelial cells. The extracellular N-terminal part of
DAF contains four short consensus repeat units (SCRs) and an STP region (serine, threonine and proline
residues).
-
Factor H consists of twenty tandemly arranged SCR units.
-
CD46 (also called MCP) is a 51–68 kDa integral membrane glycoprotein. There are two differently glycosylated
forms of MCP (58–68 kDa and 51–59 kDa, separately).
-
C1 INH is a single chain and 105 kDa plasma glycoprotein with 478 amino acid residues.
-
CD59 (also called Protectin) is a 18–25 kDa glycoprotein.
-
Vitronectin (also call S-protein) is initially synthesized as a single chain glycoprotein. One major allelic
form of vitronectin readily goes through proteolytic cleavage to yield a two-chain form.
-
Clusterin is a 70–80 kDa amphiphilic molecule and a multifunctional plasma protein that contains two
disulfide-linked chains (α and β) that are both products of one gene.
Functions of Complement Regulators
Table.2 Functions of complement regulator.
|
Regulator
|
Function
|
|
RCA/CCP family
|
CD55
|
Acceleration of C3 convertase decay.
|
|
Factor H
|
Cofactor for factor I and acceleration of alternative
pathway C3 convertase decay
|
|
CD46
|
C3 degradation, cofactor for factor I and factor H,
and effector for T cell maturation.
|
|
Others
|
C1INH
|
Blocks serine protease and is a suicide
substrate for C1r, C1s, MASP2, coagulation factors and C3b.
|
|
CD59
|
Inhibition of TCC assembly and formation.
|
|
Vitronectin
|
Binds to the nascent C5b-7, C5b-8 and C5b-9 complexes and stops their incorporation into cell
membranes.
|
|
Clusterin
|
Binds to TCC and prevents their insertion into cell membrane.
|
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