Complement:Alternative Secondary article Pathway Artice Contents Peter FZipfel,Bemhard-Nocht-Institute for Tropical Medicine,Hamburg,Germany scription of Pathwa ogical Conse ces of Co The altemative pathway of complement is a powerful and evolutionarily old defence system of innate immunity that inactivates invading microorganisms and pathogens.For survival in an immunocompetent host microbes,viruses,pathogensormodified tissue cells must provide means to interfere with and control alternative pathway reactions at severa levels Introduction tha The alternative pathway,the phylogenetically oldest and face-bound C3b in the close vicinity of the initial enzyme most importa mecha On foreign particles,unrestricted activation leads to the powerful initiation of the complement ascade,while on san further activation of this central com onent is tightly controlled by a large number of both soluble and of der sited molecules un ory prot I hes and simulta ect self cells fr Initiation the destructive effects of this defence system.If left Activation of c3 is pi otal and central to the alternative ntectious agent furnovefd bya spontancous and con induce inflammatory reactions by recruiting and stimulat- C).a molecule with acsb'-like functior occurs slowly ing immune effector cells (0.005%per min)and results from a spontaneous reaction of thioester bond with water This tickover Description of Pathway ke mo as th factor B.After enzymatic cleavage the active Bb fra The alternative pathway of complement is a host defence remains attached to C3(H2O).forming the initial C3 system that assists in maint ing the integrity of an convertase 3b(H:O)Bb H ative pathway.This ich ha removed and which exposes the highly reactive Activation thioester.The reactive C3b molecule has the ability to form ovalent bonds between its internal thioester and any ation and limited time of the reactive which leads to the formation of an enzyme complex that state ensures that activation is restricted in time e and space cleaves further C3 molecules and sets in motion an to the vicinity of newly formed molecules.Most of the thioester bonds of the activated C3(H2O)interac with f a large numbe A cleaved and activated c3h molecule is highly reactive covalently attached C3 molecules can form functional C and covalently interacts with any molecule in its vicinity convertases.allowing the activation and amplification of the pathway.w ile the initial on of C3b-generating enzymes.i.e. ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net
Complement: Alternative Pathway Peter F Zipfel, Bernhard-Nocht-Institute for Tropical Medicine, Hamburg, Germany The alternative pathway of complement is a powerful and evolutionarily old defence system of innate immunity that inactivates invading microorganisms and pathogens. For survival in an immunocompetent host microbes, viruses, pathogens or modified tissue cells must provide means to interfere with and control alternative pathway reactions at several levels. Introduction The alternative pathway, the phylogenetically oldest and most important activation pathway of the complement system, provides a highly efficient defence mechanism against invading microorganisms and bacteria. Formation of C3b occurs spontaneously and continuously, while the further activation of this central component is tightly controlled by a large number of both soluble and membrane-bound regulatory proteins. These regulators restrict activation to the surface of foreign cells and microorganisms and simultaneously protect self cells from the destructive effects of this defence system. If left uncontrolled, the activated alternative pathway deposits C3b molecules on the surface of infectious agents (microorganisms) to prepare them for phagocytosis or lysis, and the activation products (chemotactic anaphylatoxins) induce inflammatory reactions by recruiting and stimulating immune effector cells. Description of Pathway The alternative pathway of complement is a host defence system that assists in maintaining the integrity of an organism by inactivating invading organisms, pathogens and modified tissue cells. Activation Activation of the pathway starts in the fluid phase, in plasma, by a spontaneous conformational change of C3 which leads to the formation of an enzyme complex that cleaves further C3 molecules and sets in motion an amplification reaction leading to complement activation and deposition of a large number of C3b molecules on the cell surface. A cleaved and activated C3b molecule is highly reactive and covalently interacts with any molecule in its vicinity. Attachment allows powerful amplification reactions by the formation of C3b-generating enzymes, i.e. C3 convertases, that use plasma C3 as a substrate. This positive feedback amplification loop generates increasing amounts of surface-bound C3b in the close vicinity of the initial enzyme. On foreign particles, unrestricted activation leads to the powerful initiation of the complement cascade, while on self cells and tissues these reactions are tightly controlled by inhibition of enzyme complex formation and inactivation of deposited molecules. Initiation Activation of C3 is pivotal and central to the alternative pathway. It is initiated by a spontaneous and continuous turnover of fluid-phase C3, which is present in plasma in a high concentration of 1.5 mg mL 2 1 (Lambris, 1988). In human plasma, formation of C3(H2O) (also known as iC3), a molecule with a ‘C3b’-like function, occurs slowly (0.005% per min) and results from a spontaneous reaction of the internal thioester bond with water. This tickover mechanism generates a ‘C3b-like molecule’ which has the C3a part attached to the a chain and can associate with factor B. After enzymatic cleavage the active Bb fragment remains attached to C3(H2O), forming the initial C3 convertase C3b(H2O)Bb of the alternative pathway. This spontaneously formed C3(H2O)Bb molecule can generate metastable C3b, a molecule which has the C3a part removed and which exposes the highly reactive internal thioester. The reactive C3b molecule has the ability to form covalent bonds between its internal thioester and any adjacent molecule. The rapid activation and limited time of the reactive state ensures that activation is restricted in time and space to the vicinity of newly formed molecules. Most of the thioester bonds of the activated C3(H2O) interact with water and are not further active, but a small fraction interacts with nearby molecules and cell surfaces. These covalently attached C3 molecules can form functional C3 convertases, allowing the activation and amplification of the pathway. While the initial reaction occurs at a low rate, it proceeds continuously and an amplification reaction Article Contents Secondary article . Introduction . Description of Pathway . Biological Consequences of Complement Activation . Components . Control . Microbes ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 1
Complmen Ateative Pathway triggered by the activated C3(H2O)molecules induces Stabilization alternative complement pathway activation.A large r of regulatory proteins present in the fluid phase Under physiological conditions,the C3bBb complex is cel he newly gener rather unstable and dissociates irreversibly with a half-life surface of pathogens and microorganisms.but inactivate ofabout 9s.However.nthe this powerful and destructive system on the surface of host l.1954.The cells. of r erdin is mimicked in vitro by Ni?+ions which stabilize the C3bBb complex in a similar manner. Deposition of C3b Generation of AP convertase Deposition of c3bon the surface ofparticles is essential fo alternative pathway activation and the fate ofsuch surface ce er a partic attached to the C3(H-O)complex becomes accessible for (Kazatchkine)Thus. determines the fate of the newly attached C3b molecules th as to whether amplification occurs or inactivation by fragment remains attached to C3(H2O).The C3(H2O)bBb san sur 步一 tor H is a central con presence ctin/FHL-I and fad check point for this decision.In particular.surface compo les to Caand Cab The associates with factors B and D and forms AP C3 convertase C3bBb.This proteolytic prote in complex sets in on of t com inactivation. buildins further C3bBb in the surface depos tion of C3 molecules or allowing the formation of C5 convertases.which initiate the pathway.Thus Biological Consequences of feed d by ed alte mber of Car Complement Activation the fo tion molecules and a powerful amplification of the pathway Independent of its activation pathway,an amplified (Figure 1). complement cascade leads to three actions:(1)Deposition FHL-1/Reconectin C3 c36 Membrane h actor B(B) (D)int 91 rface depos .Th ENCYCLOPEDIA OF LIFE SCIENCES/001 Nature Publishing Group/www.els.net
triggered by the activated C3(H2O) molecules induces alternative complement pathway activation. A large number of regulatory proteins present in the fluid phase and on cell surfaces control the fate of the newly generated C3 molecules. They allow activation to proceed at the surface of pathogens and microorganisms, but inactivate this powerful and destructive system on the surface of host cells. Generation of AP convertase If left uncontrolled, C3b associates in the presence of Mg2 1 ions with factor B, a serine protease. Factor B attached to the C3(H2O) complex becomes accessible for another serine protease, factor D, and is cleaved to the fragments Ba (30 kDa) and Bb (60 kDa). The smaller cleavage product, Ba, is released, while the larger Bb fragment remains attached to C3(H2O). The C3(H2O)bBb complex forms the initial alternative complement C3 convertase, which in the presence of C3, factors B and D and Mg2 1 ions catalyses the cleavage of native C3 molecules to C3a and C3b. The newly generated C3b also associates with factors B and D and forms AP C3 convertase C3bBb. This proteolytic protein complex sets in motion the amplification of the alternative complement pathway by formation of more metastable C3b molecules, building further C3bBb convertases, resulting in the surface deposition of C3 molecules, or allowing the formation of C5 convertases, which initiate the lytic pathway. Thus a feedback amplification loop initiated by a spontaneously formed alternative complement pathway convertase allows the formation of a large number of C3b molecules and a powerful amplification of the pathway (Figure 1). Stabilization Under physiological conditions, the C3bBb complex is rather unstable and dissociates irreversibly with a half-life of about 90 s. However, in vivo, the complex is stabilized by properdin (factor P) which increases the half-life of the protein complex about 10-fold (Pillemer et al., 1954). The action of properdin is mimicked in vitro by Ni2 1 ions, which stabilize the C3bBb complex in a similar manner. Deposition of C3b Deposition of C3b on the surface of particles is essential for alternative pathway activation and the fate of such surfaceattached C3b is determined by the surface composition of the particle. Surface molecules influence whether a particle serves as activator or nonactivator of the pathway (Kazatchkine et al., 1979). Thus, a delicate balance determines the fate of the newly attached C3b molecules as to whether amplification occurs or inactivation by regulators and surface-bound inactivators is induced. It seems that the affinity of particle-bound C3b to its regulators, reconectin/FHL-1 and factor H, is a central checkpoint for this decision. In particular, surface components like polyanions and sialic acids determine the affinity of C3b molecules and C3bBb complexes for the negative regulators factor H and reconectin/FHL-1 and, thus, directly influence the decision towards activation or inactivation. Biological Consequences of Complement Activation Independent of its activation pathway, an amplified complement cascade leads to three actions: (1) Deposition C3 FI Cofactor activity Decay-acceleration activity FHL-1/Reconectin C3 Amplification FD Ba iC3b C3b C3b C3b C3b C3b C3b P Inactivation B Bb Bb Membrane Factor H Opsonization, Cell lysis C3b Figure 1 Formation and control of C3 at the cell surface. C3 is continuously activated by the alternative complement pathway and attaches to surfaces in the formof C3bin a random manner.Whenactivationoccurs, factorB (B)binds to C3b and is subsequentlycleaved by factor D (D) into fragmentBb and Ba. The resulting C3 convertase (C3bBb) is stabilized by binding of properdin (P) and, in an amplification loop, generates more C3b molecules which deposit in the vicinity of the convertase. A powerful amplification reaction results in surface deposition of C3b (opsonization) and formation of C5 convertases, followed by the induction of the lytic complement pathway and cell lysis. Complement regulators existing in the fluid phase and on the cell membrane determine the fate of the newly formed C3b molecule. The activity is shown here for the fluid-phase regulators factor H and reconectin/FHL-1. These regulators either direct the dissociation of the C3/C5 convertases, or they inhibit the formation of these convertases by controlling factor B binding, i.e. decay-accelerating activity. In addition, they act as cofactors for factor I and cause the inactivation of the C3b protein to the inactive form iC3b. Complement: Alternative Pathway 2 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Complement:Alternative Pathway (CR1 CR2.CR3 and CR4 with the expressed on phagocytic cells.Receptor interaction results common evolution of the individual components of the way by common structu a al ami and C5a.These anaphylatoxins are potent inducers of locations of the protein domains that provide unique inflammatory reactions.Pro-inflammatory reactions mus properties for substrate binding.protein interaction and articles and prevented on hostc membrane insertion. tions of the alternative pathway at the level of C3bBb,has to be tightly controlled.Formation,stability Effector proteins and dissociation of the plasma proteins acto d by r I(CRI/CD35).me prane cofact rotein(MCP/ ntral ele CD46)and decay-accelerating factor (DAF/CD55).The activation cascade.It is the centre where the three ound regul pathways(ie.,the ne le With a concentr cells.Due to their ins The ofaction ofthese proteins is restricted to thecell surface.In C3 allows the molecule to form covalent bonds with the widely biomolecules,cell surface components and immune com- reg plexes. has the potential to attach to a variety of d hi and the native pr bolvanions and other components matrix,factor H and reconectin/FHL-I polypeptide chai large h(Figure I .1988).Central to the fun nts of the ystems.C4 and macroglobulin.also have internal surface. lytic but un te bat memb .com tions,spo f the labelled cells and cause cell lysis This pathway in itself is than1%make the thi attack by nearby nucleophilic groups These reactions tightly controlled:again.several fluid-phase and surface ow the glutamine residues to eac und regu limit activation and pore formation bound xyl or amino gr oups to an c ther mo all three In the alter complement pathway, a spontaneously formed C3(H2O)Bb protein is the first convertase and provides Components on sof particles.In its default setting The complement proteins are a prime example of proteir families with diverse,but overlapping,functional proper this reaction results in an unrestricted and excessive structurale amplincation of the complement cascade. ments. at山 genes Activation of C3 Spontaneous conformational changes in C3 directly ification and exon shuffling.Most of the complement expose the internal thioester bond,making it accessible ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net
of and coating of C3b molecules on foreign cells or particles (opsonization) that allows binding and interaction of several cellular C3 receptors (CR1, CR2, CR3 and CR4) expressed on phagocytic cells. Receptor interaction results in rapid and efficient phagocytosis of these particles. (2) The initiation of the lytic pathway by formation of the membrane attack complex. (3) Pro-inflammatory reactions induced by the release of the cleavage products C3a and C5a. These anaphylatoxins are potent inducers of inflammatory reactions. Pro-inflammatory reactions must be restricted to foreign particles and prevented on host cells and tissues. Thus, activation, in particular the initial reactions of the alternative pathway at the level of C3b and C3bBb, has to be tightly controlled. Formation, stability and dissociation of the complexes is regulated by the plasma proteins factor H and reconectin/FHL-1 and by three membrane-bound proteins called complement receptor 1 (CR1/CD35), membrane cofactor protein (MCP/ CD46) and decay-accelerating factor (DAF/CD55). The membrane-bound regulators are expressed by a wide range of cells and tissues and CR1/CD35,MCP/CD46 and DAF/ CD55, are present on almost all human peripheral blood cells. Due to their insertion into the cell membrane, the site of action of these proteins is restricted to the cell surface. In contrast, action of the widely distributed fluid-phase regulators (factor H and reconectin/FHL-1) is not limited to the cell membrane, but occurs in the fluid phase and at the extracellular matrix. By interacting with sialic acids, polyanions and other components of the extracellular matrix, factor H and reconectin/FHL-1 can control a larger area surrounding the cell surface. Thereby, these plasma proteins control C3b formation and reduce the number of C3b molecules that attach directly to the cell surface. Alternative complement activation initiates the lytic pathway, i.e. the formation of membrane attack complexes that incorporate holes in the plasma membrane of the labelled cells and cause cell lysis. This pathway in itself is tightly controlled; again, several fluid-phase and surface bound regulators control the individual reaction steps of this pathway and limit activation and pore formation to foreign cells and particles. Components The complement proteins are a prime example of protein families with diverse, but overlapping, functional properties defined by conserved common structural elements. The structure and organization of the genes coding for the complement proteins emphasize that the evolution of new protein function occurs via gene duplication, gene modification and exon shuffling. Most of the complement proteins show a modular, multidomain structure and several of the genes are tightly linked in gene clusters (Hourcade et al., 1992). The modular composition of the exons and the conservation of structural domains in proteins with related functions is consistent with the common evolution of the individual components of the complement system. The conserved protein domains display common three-dimensional structures which are defined by conserved and structurally essential amino acid residues and amino acid substitutions at surface-exposed locations of the protein domains that provide unique properties for substrate binding, protein interaction and membrane insertion. Effector proteins C3 The plasma glycoprotein C3 (183 kDa) is the pivotal complement component and the central element of the activation cascade. It is the centre where the three complement activation pathways (i.e. the alternative, the classical and the lectin pathway) merge. With a concentration of 1.0–1.5 mg mL 2 1 , C3 is one of the most abundant human plasma proteins. The intramolecular thioester of C3 allows the molecule to form covalent bonds with biomolecules, cell surface components and immune complexes. Thus, C3 has the potential to attach to a variety of molecules and bind to various targets. C3 is synthesized as single-chain precursor and the native protein is composed of two disulfide-bonded polypeptide chains: the 115-kDa a chain and the 75-kDa b chain (Figure 2; Lambris, 1988). Central to the function of C3 is the internal thioester bond formed between Cys988 and Gln991. Two other components of the complement systems, C4 and a2-macroglobulin, also have internal thioester bonds. In the native C3 protein, this site is not accessible, but under physiological conditions, spontaneous conformational changes occurring at a rate of less than 1% make the thioester reactive and accessible to attack by nearby nucleophilic groups. These reactions allow the glutamine residues to react covalently via hydroxyl or amino groups to any other molecule. C3 activation is initiated by the C3 convertases formed in all three complement activation pathways. In the alternative complement pathway, a spontaneously formed C3(H2O)Bb protein is the first convertase and provides the source for an amplification reaction leading to formation of further convertases and deposition of C3b molecules on the surfaces of particles. In its default setting, this reaction results in an unrestricted and excessive amplification of the complement cascade. Activation of C3 Spontaneous conformational changes in C3 directly expose the internal thioester bond, making it accessible for nucleophilic attack by either H2O or nucleophiles, such as amine or hydroxyl groups. In a newly formed C3b Complement: Alternative Pathway ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 3
Pathway 5-C-O complement components which are not accessible in the c3 molecule.The thioester of the newly formed metastable C3 site Bind: e0 to newly formed C3b either leads to generation of the C3 convertases and amplification reactions by interaction iacroinactiation FHL-L C4R reconectin Table I to be inserted here C3 Role of c3-degradation products several cofactor molecules for its activity (Figure 2 and Table 1).The cofactors induce conformational changes in and mad in ble for t I+cofactor ns con longer participates in comp nent activation Eurthe C3dg cleavage of the achain forms the fragments C3c and C3dg ragment re C3 fragments that are generated during complement activation bind specifically to several surface receptors The hindi ☐c3g c3d C3 fragments to their specific receptors results in a variety fragments s the rele 3in the In addition,multiple complement receptors rec ognize c3 fragments on the surface of particles and local interaction phagocytosis and elimination of the coated 边恤9n出t6a Factor B molecule this thioester is with Cb makes the proten (60 us)before the molecule is inactivated.This short hal the rele ed Ba fr ment (33kDa)is r life restricts alternative pathway activation locally and,in by three short consensus repeat (SCR)domains.which are ds within the immedi 60k )iser an C?h resulting in release of the anaphylactic C3a fragn Each of the fun nally relevant domains of the active sit The newly formed C3b expresses multiple binding sites for is contained on a separateexon.factor bof the alternative ENCYCLOPEDIA OF LIFE SCIENCES/2001Na
molecule, this thioester is exposed for a brief period of time (60 ms) before the molecule is inactivated. This short halflife restricts alternative pathway activation locally and, in time, ensures that activation proceeds within the immediate vicinity. Both the classical and alternative complement convertases cleave C3 between Arg726 and Ser727, resulting in release of the anaphylactic C3a fragment. The newly formed C3b expresses multiple binding sites for complement components which are not accessible in the C3 molecule. The thioester of the newly formed metastable C3b molecule is highly reactive, allowing attachment of the C3b proteins to nearby molecules and surfaces close to the site of activation. Binding of the complement components to newly formed C3b either leads to generation of the C3 convertases and amplification reactions by interaction with factor B, factor D and properdin, or to inactivation of C3b by MCP (CD46), CR1 (CD35), factor H, reconectin/ FHL-1, C4bp or factor I (Figure 2 and Table 1). Table 1 to be inserted here Role of C3-degradation products C3b is inactivated by factor I, which cleaves the protein at several sites within the a chain and which requires one of several cofactor molecules for its activity (Figure 2 and Table 1). The cofactors induce conformational changes in C3b and make the molecule accessible for the protease. C3 is degraded in an orderly manner and the various degradation fragments serve distinct biological functions. The first cleavage by the specific protease factor I, together with a cofactor, produces iC3b and a 2-kDa C3f fragment, which is liberated. This conversion results in a conformational change of the protein and the inactivated iC3b no longer participates in complement activation. Further cleavage of the a chain forms the fragments C3c and C3dg. As the thioester site is contained within the C3dg fragment, the C3dg fragment remains attached to the surface, while the C3c fragment is released. Surface-bound and soluble C3 fragments that are generated during complement activation bind specifically to several surface receptors expressed on a number of immune effector cells, such as CR1 (CD35), CR2 (CD21), CR3 (CD11b,CD18), CR4 (CD11c,CD18) and C3a receptor (Table 1). The binding of C3 fragments to their specific receptors results in a variety of biological responses. In particular, the anaphylatoxin C3a triggers the release of soluble inflammatory mediators, such as histamine, and serves as a chemotactic factor which attracts immune effector cells to the site of inflammation. In addition, multiple complement receptors recognize C3 fragments on the surface of particles and local interaction induces phagocytosis and elimination of the coated particle. Factor B Factor B is a single-chain, 93-kDa polypeptide. Its association with C3b makes the protein susceptible for proteolytic cleavage by factor D. The smaller cleavage product, the released Ba fragment (33 kDa), is represented by three short consensus repeat (SCR) domains, which are each encoded by a separate exon. The larger Bb fragment (60 kDa) is encoded by 13 exons and contains domains with homology to the catalytic chains of other serine proteases. Each of the functionally relevant domains of the active site is contained on a separate exon. Factor B of the alternative SC O S S SS + + + AP convertase S S H SC O SS Factor I + cofactor Factor I + cofactor H SC O SS S S S S SS Trypsin H SC O H SC O C3a C3f C3c C3d C3dg iC3b C3b C3 Surface attached fragments Liberated fragments α β C3g Figure 2 Processing of C3 in the alternative pathway. A continuously and spontaneously formed C3 convertase cleaves plasma C3 to C3b and the anaphylactic C3a fragment. The thioester of C3b interacts with molecules in its vicinity and binds to cell surfaces. C3b is inactivated by factor I in combination with various cofactors in several steps. The first cleavage results in the inactive form of iC3b and the release of fragment C3f. A second cleavage liberates the large C3c fragment and leaves the smaller C3dg fragment attached to particles or biomolecules. Further cleavage forms the C3d fragment. The various fragments represent ligands for several C3-binding proteins and specific C3 receptors. Complement: Alternative Pathway 4 ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net
Complement:Alternative Pathway Table 1 Components of the alternative pathway Molecular weight Plasma concentration Protein Function (kDa) (ug mL) Domain structure Activators C3 Central component 1000-1600 Thioester Factor B Serine protease 93 200 Ba SCR Bb serin Factor D Serine protease 24 2 Serin proteas Properdin Stablilizers C3 and C5 convertases 53 25 Regulators-soluble Factor I Inactivation of C3b in the 88 35 Serine presence of cofactors protease serine prot Factor H 15 c.500 SCR Reconectin/FHL-1 25-50 Bb:Cofactor for adhesion SCR molecule FHR-1 37,42 SCR FHR2 24.29 FHR-3 C3-binding protein 34-56 FHR-4 C3-binding protein 86 Regulators-membrane bound CRI (CD35) Accelerates decay of C3b, 190(most SCR Bb,cofactor for I lotype DAF(CD55) Accelerates decay of C3b,Bb MCP(CD46) Cofactor for I 4568 SCR.short-consensus repeat stabilize the alternative complement pathway con th al patnway reg olymers consisting of tetramersand trimers.composed of Factor D several subunits of 53kDa which bind to each other in a The rine protease factor D is a 24-kDa single-chair motifs in an active form.The human protein displays a 60% Plasma regulators Factor I 五actolicmmciaeheaiPreaacapndnci Factor i mber of the serir Properdin pathway by cleaving C3b and C4b.Factor I is a central ne eral..19/ ENCYCLOPEDIA OF LIFE SCIENCES/2001 Nature Publishing Group /www.els.net 5
complement pathway shows structural and functional homology to the classical pathway regulator C2. Factor D The serine protease factor D is a 24-kDa single-chain protein present in human plasma at a rather low concentration. Apparently factor D circulates in plasma in an active form. The human protein displays a 60% amino acid homology to mouse adipsin, a mouse serine protease expressed in adipocytes which functions in lipid metabolism. Properdin Properdin was the first of the alternative pathway proteins to be identified (Kazatchkine et al., 1979). Its function is to stabilize the alternative complement pathway convertase. In plasma, the properdin glycoprotein appears in cyclic polymers consisting of tetramers and trimers, composed of several subunits of 53 kDa which bind to each other in a head to tail fashion. Each subunit contains repeating motifs of the thrombospondin type 1 repeats. Plasma regulators Factor I Factor I is a member of the serine protease family and acts in both the alternative and the classical complement pathway by cleaving C3b and C4b. Factor I is a central complement regulator and several cofactors are essential for its proteolytic degrading activity. The protein is Table 1 Components of the alternative pathway SCR, short-consensus repeat. Protein Function Molecular weight (kDa) Plasma concentration (µg mL–1) Domain structure Activators C3 Central component 1000–1600 Thioester Factor B Serine protease 93 200 Ba SCR Bb serine protease Factor D Serine protease 24 2 Serine protease Properdin Stablilizers C3 and C5 convertases 53 25 Regulators – soluble Factor I Inactivation of C3b in the presence of cofactors serine protease 88 35 Serine protease Factor H Accelerates decay of C3b, Bb; Cofactor for I; Binding to host cells, adhesion molecule 155 c. 500 SCR Reconectin/FHL-1 Accelerates decay of C3b, Bb; Cofactor for I; adhesion molecule 25–50 SCR FHR-1 ? 37, 42 SCR FHR-2 ? 24, 29 FHR-3 C3-binding protein 34–56 FHR-4 C3-binding protein 86 Regulators – membrane bound CR1 (CD35) Accelerates decay of C3b, Bb; cofactor for I 190 (most common allotype) SCR DAF (CD55) Accelerates decay of C3b, Bb 70 SCR MCP (CD46) Cofactor for I 45–68 SCR Complement: Alternative Pathway ENCYCLOPEDIA OF LIFE SCIENCES / & 2001 Nature Publishing Group / www.els.net 5