Complemen Regulation of C3 convertase Cases of hereditary deficiencies have been described for Binding of DAF,a membrane-bound protein,to C4b in C3 each of the components Clq.CIr.Cls.C4.C2,and C3 of the cl ical activation pathway.and th faofcontrol Streptococcus)and to immune complex disease such as of factor I leads to the formation of bimolecular associa hibitor isas ed the may cause fatalobstruction of the upper airways.Inherited deficiency of the membrane regulatory component DAF is racte by par noctur proteolysis by factor I, suppressing the activity of the oxysma catabolism leading to uncontrolled C3 cleavage by the alternative pathway C3 convertase esis is the FactorI e hepatocyte. nd lov increased susceptibility to recurrent bacterial and viral and a po ic residues linking the two ca chains in profactor I.Its high carbohydrate conten dete tof e MBL ev ton of the six pot modu minal end followed by a scavenger receptor cysteine-rich(SRCR) two low-density lipoprotein receptor class A Phylogeny )modules,and a serine protease domai (Figure Opsonic complement activities have been found in all vertebrate species tested,from the mammals back to the hsh (sharks and ed to lke proteins in th Protein Biosynthesis and Deficiencies a lectin pathway in this es which is inter between vertebrates and invertebrates.Current phyloge netic knowledge provide s support to the hypothesi complement arose as an innate system,possit antibodies.Contrary to the old view that complement Ive ompon 'complements'the adaptive immune system,it may be cells considered that antibodies arose to'complement'comple- cells,leukocytes,ete.)produce complement proteins ment by increasing its versatility i Evidence is also e References those shielded from pl onents by blood-tissu Arlaud GJ.Colomb MG and GagnonJ(1987)A functional modelofthe barriers.Thus,the cells of the central nervous system biosynthesize a complete,functional c stem and express com ors ar Coope une defenee but r ably also has NR(15)The classical complement pathway:activation and t complement implications in inflammatory and degenerative diseases. 0gy37:151-216 8 ENCYCLOPEDIA OF LIFE SCIENCES/2001 Na shing Group /www.els.neRegulation of C3 convertase Binding of DAF, a membrane-bound protein, to C4b in C3 convertase leads to increased decay of the convertase, an activity facilitated by the glycolipid anchor of DAF, which confers to this protein a large area of control on the cell membrane. Destabilization of C3 convertase by cofactors of factor I leads to the formation of bimolecular associa￾tions between C3b or C4b and one of the cofactors, which are soluble proteins (C4BP for the cleavage of C4b, factor H for the cleavage of C3b) or membrane-associated proteins (MCP and receptor CR1). Under their associated forms, C3b and C4b become available as substrates for proteolysis by factor I, suppressing the activity of the convertase. C4b ligands like C4BP and DAF are also able to bind C4b alone and thereby interfere with C3 convertase assembly. Factor I The mature protein in blood consists of two disulfide￾linked 50-kDa and 38-kDa polypeptide chains, the latter being a serine protease domain. Maturation results from intracellular removal of four basic residues linking the two chains in profactor I. Its high carbohydrate content corresponds to a probable glycosylation of the six potential sites in the sequence. Factor I exhibits a unique modular structure, with a factor I/membrane attack complex proteins C6/7 (FIMAC) module at the N-terminal end, followed by a scavenger receptor cysteine-rich (SRCR) module, two low-density lipoprotein receptor class A (LDLRA) modules, and a serine protease domain (Figure 1). Protein Biosynthesis and Deficiencies The major site of biosynthesis for most of the circulating complement components is the hepatocyte, and more than 90% of serum complement proteins is produced in the liver. However, C1 subcomponents are synthesized pri￾marily in the gut epithelium, and a growing list of other cells (monocytes/macrophages, fibroblasts, endothelial cells, leukocytes, etc.) produce complement proteins. Evidence is also emerging that locally produced comple￾ment proteins might be an important factor in triggering inflammation in different peripheral tissues, especially those shielded from plasma components by blood–tissue barriers. Thus, the cells of the central nervous system biosynthesize a complete, functional complement system and express complement regulators and receptors. Com￾plement biosynthesis in the brain is thought to be important in immune defence but probably also has implications in inflammatory and degenerative diseases. Cases of hereditary deficiencies have been described for each of the components C1q, C1r, C1s, C4, C2, and C3 of the classical activation pathway, and these deficiencies are generally associated with an increased susceptibility to infection by pyogenic microorganisms (Staphylococcus, Streptococcus) and to immune complex disease such as systemic lupus erythematosus (Morgan and Walport, 1991). Deficiency of C1 inhibitor is associated with hereditary angioedema, which is probably due to the kinin-like activity of a fragment released from C2b, and may cause fatal obstruction of the upper airways. Inherited deficiency of the membrane regulatory component DAF is characterized by paroxysmal nocturnal haemoglobinuria, whereas deficiency of either factor I or factor H results in a state of acquired C3 deficiency, due to the lack of C3b catabolism leading to uncontrolled C3 cleavage by the alternative pathway C3 convertase. The major site of MBL biosynthesis is the hepatocyte. Levels of MBL in serum show a wide range (0–5 mg L 2 1 ), and low serum concentrations are found associated with increased susceptibility to recurrent bacterial and viral infections. There are three common structural alleles of MBL, each characterized by a single point mutation in the collagen-like region, and these are the most important determinants of the MBL level. Phylogeny Opsonic complement activities have been found in all vertebrate species tested, from the mammals back to the cartilaginous fish (sharks and rays). More recent studies have led to identification of MASP-like proteins in the urochordate Halocynthia roretzi, suggesting occurrence of a lectin pathway in this species which is intermediate between vertebrates and invertebrates. Current phyloge￾netic knowledge provides support to the hypothesis that complement arose as an innate defence system, possibly based on lectin recognition, before the emergence of antibodies. Contrary to the old view that complement ‘complements’ the adaptive immune system, it may be considered that antibodies arose to ‘complement’ comple￾ment by increasing its versatility in recognition. References Arlaud GJ, Colomb MG and Gagnon J (1987) A functional model of the human C1 complex. Immunology Today 8: 106–111. Bork P and Bairoch A (1995) Extracellular protein modules: a proposed nomenclature. Trends in the Biochemical Sciences 20 (Supplement March), C03. Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Advances in Immunol￾ogy 37: 151–216. Complement: Classical Pathway 8 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net