Control mechanisms

The activation of the classical pathway has multiple control mechanisms. The proteolytic activity of activated CI is controlled by Cl-inh, which irreversibly activates Clr and Cls. It is also a physiological inhibitor of kallikrein and activated factors XII and XI. Cl-inh is a 100-110 kDa single polypeptide chain protein, containing about 50% carbohydrate. It is homologous to other serpins, such as antithrom-bin III. It acts as a pseudosubstrate for the proteases which it inhibits: these cleave an Arg-Thr bond 34 residues from the C-terminus of Cl-inh, but Cl-inh remains covalently bound to the protease, probably by an ester bond formed by the arginine carbonyl and the active-site serine of the protease. Cl-inh attacks activated CI by first reacting with Cls, then with Clr: the Clr2Cls2 complex dissociates to form two Clinh-Clr-Cls-Clinh complexes, which no longer bind to Clq. Clq, still bound to the complement activator, can now bind to Clq receptor, or can participate in a further slow cycle of binding, activation and inactivation of Clr2Cls2. MASP-1 is also inhibited by Cl-inh, but this has not been investigated for MASP-2.

The C3 and C5 convertase enzymes are also subject to control: one aspect of control is the inefficiency of binding of nascent C4b and C3b to appropriate sites to form the convertases. Once formed, the convertases are unstable: C2a dissociates from C4b or C4b3b with a half-life of 2-5 min. Once C2a has dissociated, more C2 can bind to C4b, but the adjacent CI molecule required to cleave the C2 may already have been inactivated. The stability of the convertases is further decreased by a group of control proteins which includes the plasma proteins factor H and C4bp, and the membrane proteins CR1, MCP and DAF. These proteins, together with CR2, are composed mainly, or only of CCP domains, and are all encoded by genes in the RCA (regulation of complement activation) cluster on human chromosome lq31-32.

CR1, DAF and C4bp bind to C4b2a or C4b2a3b and cause C2 to dissociate: they also compete with C2 for the initial binding to C4b. CR1 and C4bp, and also MCP, once bound to C4b, render C4b susceptible to attack by the control serine protease, factor I, which cleaves at two sites in the a chain of C4b, forming C4c (145 kDa) and C4d (45 kDa), which no longer participate in convertase formation. CR1 and MCP also act as cofactors for the factor I-mediated cleavage of C3b to form iC3b, as does factor H. In the alternative pathway, CR1, DAF and factor H accelerate the decay of the C3 convertase,

Table 2 Properties of classical pathway proteins

Protein

Mol. wt (kDa)

Chromosomal localization of gene

Plasma concentration (i±g ml ~1)

Components

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