Compleme Altemaive Pathway composed of two disulfide bond chains of 50 and 38 kDa FHR-2 as a 27-and 24-kDa.The FHR-3 protein is present and several carbohydrates are attached to the secreted n se everal glycosylated forms ranging from 49 to 58 kDa. alinelteDmroteinhasamodnlarcomposi on and the B all of whick chain possesses a serine protease structure. (Regulators of Complement Activation)gene cluster.The precise function of the various proteins is under investiga Factor H Factor H is a single-chain,155-kDa glycoprotein that is homolog othe FHR 0μgmL Zipfe activity and control the fate of the protein is sh cdomansem Membrane-bound regulators domain,multifunctional protein with regulatory activities in the complement system and has additional functions The thre membrane-boundof the a ent nathway helong er with other comnle outside of the complement system. complement ment control proteins,to the regulators of complement the SCR 1 4. ct me I(region sufficient for cofactor and decay-acceleration activity. Additional functional domains have been identified withir SCR the intact mol ule,in ding a total of three C3-binc membrane-bound regulators.they serve imp tantcontrol function in both the alternative and the classical comple Gly-Asp )which is a ma ment pathway. adhesion proteins for interaction with integrin typ CR1 receptors.Factor H sbeen shown (CD ment receptor L-selectin comple eriphera CRIs al h Reconectin/FHL-1 SCR are arranged in long alternative processing.Expression of the two transcripts is way 84502 regulated nd22-28).Within cach a tissue- reconectin/FHL A is th r and repeat domain.the binding sites for the ligands are located within the N-terminal par sCR factor H with fou rt,providing also the basis for additiona multiple interaction sites for C3b. amino acids added to the C-terminal end.Reconectin/ FHL-I is a multidomain multifunctional protein and acts Membrane cofactor protein (MCP/CD46) e ay a The mem rane co actor p ein (MCP)is a mem 1999).In addition tothe conse proteins.The N N-terminal SCR 1-4,the protein includes a heparin terminal extracellular domain of MCP is compo sed of four binding domain in SCR 7and the RGD-adhesion domain, CR domains that are followed by a stretch of serine. oca within SCR s attachment to cell surlace threonine and proline resid lues (ST 10-50L f MCP) ymor hic as due to alte action of this protein is suggested due to its smaller size that splicing of an exon. results in fast diffusion. Decay accelerating factor(DAF/CD55) Factor H-related proteins(FHRs) The decay-accelerating protein is a membrane-bound d proteins(FHR-1 to FHR-4)repre that controls the formation and rs of the tein far uces t CR skerka 1994) vely 0- svlated stp re and a stretch o The FHR-I protein exists asa43-and 37-kDa protein.and 24 hydrophobic residues.The protein is attached to the 6 shingGroup/www.els.netcomposed of two disulfide bond chains of 50 and 38 kDa and several carbohydrates are attached to the secreted protein. The protein has a modular composition and the b chain contains two low-density lipoprotein receptor repeats, and a repeat shared with C6 and C7. The light chain possesses a serine protease structure. Factor H Factor H is a single-chain, 155-kDa glycoprotein that is present in human plasma in a concentration of about 500 mg mL 2 1 (Zipfel and Skerka, 1994). The secreted form of the protein is composed of 20 repetitive domains termed short consensus repeats (SCRs). Factor H is a multi￾domain, multifunctional protein with regulatory activities in the complement system and has additional functions outside of the complement system. The complement regulatory domains have been localized to the N-terminus of the protein and SCRs 1–4 are both essential and sufficient for cofactor and decay-acceleration activity. Additional functional domains have been identified within the intact molecule, including a total of three C3-binding domains, three heparin-binding domains, and the amino acid motif RGD (Arg-Gly-Asp), which is a major site of adhesion proteins for interaction with integrin type receptors. Factor H has been shown to bind to the integrin-type receptor Mac-1 (CD11b/CD18, or comple￾ment receptor CR3) and to L-selectin. Reconectin/FHL-1 The factor H-like protein 1 (FHL-1), also termed reconectin, is derived from the factor H gene by means of alternative processing. Expression of the two transcripts is regulated in a tissue- and mediator-specific way and apparently the reconectin/FHL-1 mRNA is the default transcript. The corresponding protein represents the N￾terminal seven SCRs of factor H with four additional amino acids added to the C-terminal end. Reconectin/ FHL-1 is a multidomain multifunctional protein and acts as a regulator of the alternative complement pathway and also displays cell adhesion functions (Zipfel and Skerka, 1999). In addition to the conserved complement regulatory N-terminal SCR 1–4, the protein includes a heparin￾binding domain in SCR 7 and the RGD-adhesion domain, located within SCR 4, confers attachment to cell surface receptors of the integrin type. The plasma concentration of reconectin/FHL-1 is about 10–50 mg mL 2 1 and a local action of this protein is suggested due to its smaller size that results in fast diffusion. Factor H-related proteins (FHRs) The factor H-related proteins (FHR-1 to FHR-4) repre￾sent additional members of the factor H protein family and are present in human plasma and in lipoproteins in differently glycosylated forms (Zipfel and Skerka, 1994). The FHR-1 protein exists as a 43- and 37-kDa protein, and FHR-2 as a 27- and 24-kDa. The FHR-3 protein is present in several glycosylated forms ranging from 49 to 58 kDa, and the FHR-4 protein exists in plasma and in lipids as a dimeric glycoprotein of 87 kDa. Each protein is encoded by a unique gene, all of which seem located within the RCA (Regulators of Complement Activation) gene cluster. The precise function of the various proteins is under investiga￾tion. In addition to their structural and sequence homology and their immunological crossreactivity with factor H and reconectin/FHL-1, the FHR proteins display cofactor activity and control the fate of C3. Membrane-bound regulators The three membrane-bound regulators of the alternative complement pathway belong, together with other comple￾ment control proteins, to the regulators of complement activation gene cluster on human chromosome 1 (region 1q32). The three proteins are structurally related, as their extracellular region is composed of SCR domains, and as membrane-bound regulators, they serve important control function in both the alternative and the classical comple￾ment pathway. CR1 CR1 is a single-chain membrane protein involved in complement regulation, as it displays cofactor and decay￾accelerating activity. Expressed in nearly all human peripheral blood cells, CR1 is a highly polymorphic protein and, in the most dominant form, is composed of 30 SCR domains. The SCRs are arranged in long homologous repeats, each containing seven contiguous SCRs (i.e. SCRs 1–7, 8–14, 15–21 and 22–28). Within each repeat domain, the binding sites for the ligands are located within the N-terminal part, providing also the basis for multiple interaction sites for C3b. Membrane cofactor protein (MCP/CD46) The membrane cofactor protein (MCP) is a membrane￾bound regulator that has cofactor activity for factor I in the degradation of membrane-attached C3b proteins. The N￾terminal extracellular domain of MCP is composed of four SCR domains that are followed by a stretch of serine, threonine and proline residues (STP region) and a transmembrane region. In the case of MCP, the STP region occurs in polymorphic forms due to alternative splicing of an exon. Decay accelerating factor (DAF/CD55) The decay-accelerating protein is a membrane-bound complement regulator that controls the formation and reduces the stability of membrane-attached convertases. The protein is composed of four SCR domains followed by an extensively O-glycosylated STP region and a stretch of 24 hydrophobic residues. The protein is attached to the Complement: Alternative Pathway 6 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net