Complement membrane via a covalent linkage to a glycosylphosphati- to ic3b.C3dg and C3d fragments of C3.It also binds to dylinositol(GPD)and may be involved in signal transduc gp350.an Epstein-Barr virus envelope glycoprotein,and tion.The role of DAF is to d the binding of the ell surtg CZa or iva 45 to 75kDa.depending on the degree of glycosylation. erminal centres.CR2is implicated in the regulation of B cell responses and is involved in antibody responses to T- cell-dependent and-independent a -me DaF MCP is devoid of ded accelerating activity g to the leucocyte-integrin family CD59 is an 18-20-kDa GPI-linked membrane proteir s not contain any SCR modules which bindstond C and inhibits the formation ofthe (LFA-Dand(CR).whereas (CD11b)is a type I transmembrane glycoprotein that is valentlv with the B chain.CR3 binds Complement Receptors to the form of C3 in a diy C1q receptors h ide.zymosan.soluble Fey receptor Leis/imania s have be ops on an A (SP A interacts with cla roxide reseh gqR characterized receptor,is a Complement receptor type 4(CR4.CDIle/CD18)is kDa type I membr From the N adhesion EGF-like modules and s very s a cytoplasmic tyrosine phosphorylation motif that is role of CRis not clear.but its prop rties may be similar to activation signals those of CR3 MBL orSP-A-cmtaining C3a and C5a anaphylotoxin receptors are members of or involved in C3/C4 receptors release of lysosomal contents CD35)is a type presents four different allotypes with different molecula Functions of the Complement System 5 y as a tor for of the s biomp ent syst pManhi ngly than doe system plays very important roles in the following. Opsonization of foreign material (1)As a regu iatedry prote This s involves the c and it also has decay. activity for the C3 convertase.(2)As a receptor,CRI promotes the binding The opsonized surface becomes a target that can then be and phagocytosis of C3 and C4 phagocytic cel and also invo arance or type 2(CR2.CD21 or C3d/EBV receptor)is a 140-kDa membrane glycoprotein that binds ENCYCLOPEDIA OF LIFE SCIENCES/62001 N www.els.net >membrane via a covalent linkage to a glycosylphosphati￾dylinositol (GPI) and may be involved in signal transduc￾tion. The role of DAF is to dissociate the C3 and C5 convertases by releasing C2a or Bb from the convertases. MCP is a single-chain glycoprotein that ranges in size from 45 to 75 kDa, depending on the degree of glycosylation. MCP is present in four different isoforms in humans. Like DAF,MCP contains four SCRs, but it differs from DAF in that it serves as a cofactor for factor I-mediated cleavage of C3b and C4b deposited on self tissue; also in contrast to DAF, MCP is devoid of decay-accelerating activity. CD59is an 18–20-kDa GPI-linked membrane protein which binds to C8 and C9and inhibits the formation of the MAC on host cells. Complement Receptors C1q receptors Three molecules have been shown to act as C1q receptors. cC1qR is a calreticulin-like molecule that also binds to MBL or surfactant protein A (SP-A). C1qR02 only interacts with C1q and appears to trigger superoxide production. C1qRp, the best characterized receptor, is a 66.5-kDa type I membrane glycoprotein. From the N￾terminus to C-terminus C1qRp is composed of a C-type lectin domain (CRD domain), five EGF-like modules, and a cytoplasmic tyrosine phosphorylation motif that is involved in transducing cellular activation signals. C1qRp is also important in mediating phagocytic processes following binding of C1q, MBL or SP-A-containing complexes. C3/C4 receptors Complement receptor type 1 (CR1 or CD35) is a type I transmembrane glycoprotein of 220 kDa that contains 30 SCRs and is present in a wide variety of cells (Table 2). CR1 presents four different allotypes with different molecular masses of 160 (C form), 190 (A form), 220 (B form) and 250 (D form) kDa. It functions mainly as a receptor for C3b and C4b, although it binds with lesser affinity to iC3b and C3c. Multivalent C3b binds more strongly than does monovalent C3b, a difference which might have physiolo￾gical relevance for the CR1-mediated functions. CR1 has two functions: (1) As a regulatory protein, it serves as a cofactor for the factor I-mediated cleavage of C3b or C4b, and it also has decay-accelerating activity for the C3 convertase. (2) As a receptor, CR1 promotes the binding and phagocytosis of C3b- and C4b-coated particles by phagocytic cells, and is also involved in the clearance of immune complexes. Complement receptor type 2 (CR2, CD21 or C3d/EBV receptor) is a 140-kDa membrane glycoprotein that binds to iC3b, C3dg and C3d fragments of C3. It also binds to gp350, an Epstein–Barr virus envelope glycoprotein, and mediates the binding of the virions at the cell surface. CD23, a low-affinity receptor for IgE, also binds to CR2, an interaction that may influence the survival of B cells in germinal centres. CR2 is implicated in the regulation of B￾cell responses and is involved in antibody responses to T￾cell-dependent and -independent antigens. Complement receptor type 3 (CR3, CD11b/CD18), with a 170-kDa a chain and a 95-kDa b chain, is an adhesion molecule belonging to the leucocyte–integrin family. Unlike CR1 or CR2, it does not contain any SCR modules. The b chain of CR3 (CD18) is common to other members of the leucocyte–integrin family such as CD11a/CD18 (LFA-1) and CD11c/CD18 (CR4), whereas the a chain (CD11b) is a type I transmembrane glycoprotein that is associated noncovalently with the b chain. CR3 binds specifically to the iC3b form of C3 in a divalent cation￾dependent manner. It also binds to several other molecules, such as coagulation factor X, fibrinogen, lipopolysacchar￾ide, zymosan, soluble Fcg receptor III, Leishmania promastigote surface glycoprotein gp63, and others. When iC3b serves as the ligand, CR3 mediates opsonization and phagocytosis of microorganisms, as well as enhancement of natural killer (NK) cell activity for C3-coated targets. Complement receptor type 4 (CR4, CD11c/CD18) is also an adhesion molecule of the leucocyte–integrin family. It is very similar to CR3, and it also binds iC3b in a divalent cation-dependent manner. The physiological role of CR4 is not clear, but its properties may be similar to those of CR3. C3a and C5a anaphylotoxin receptors are members of the superfamily of rhodopsin-type receptors, which con￾tain seven transmembrane loops. C3aR (95 kDa) and C5aR (43 kDa) are involved in a variety of processes, including chemotaxis, cell aggregation and adhesion, and release of lysosomal contents. Functions of the Complement System Activation of the complement system results in the initiation of various biological processes. The complement system plays very important roles in the following. Opsonization of foreign material This process involves the covalent binding of C3b and/or C4b to viruses, bacteria, fungi and other microorganisms. The opsonized surface becomes a target that can then be recognized and engulfed by phagocytic leucocytes bearing C3b or C4b receptors on their surfaces. Complement ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 7