Figure 1. An overview of complement activation, regulation and diseases caused by deficiencies of complement regulator proteins. The C1r and C1s are serine esterases that are inhibited by the plasma protein C1 inhibitor (C1 INH). C1 INH also inhibits analogous MBL-associated serine protease, MASP-2. Activity of the classical pathway C3/C5 convertase, C4b2a, is inhibited by the plasma factor C4b-binding protein (C4bp). The activity of the alternative pathway C3/C5 convertase, C3bBb, can be enhanced by the only known physiological positive complement regulator, properdin (P). The self-amplifying process of the AP is inhibited by multiple regulator molecules described in Figure 2. The five terminal plasma glycoproteins (C5, C6, C7, C8 and C9) bind sequentially to each other to generate the cytolytic membrane attack complex (MAC). Soluble regulators S-protein and clusterin keep forming terminal C complexes in the fluid phase. On human cell membranes the main inhibitor of MAC is CD59 (protectin). Consequences of major complement regulator deficiencies are indicated by broken arrows. HAE, hereditary angio-oedema; PNH, paroxysmal nocturnal haemoglobinuria; MPGN, membranoproliferative glomerulonephritis; aHUS, atypical haemolytic uraemic syndrome and AMD, age-related macular degeneration.

Figure 2. Regulators of the classical (CP) and alternative (AP) pathways of complement. Membrane regulators include decay-accelerating factor (DAF; CD55), complement receptor type 1 (CR1; CD35), complement receptor of the immunoglobulin superfamily (CRIg) and membrane cofactor protein (MCP; CD46). Soluble regulators include C1 inhibitor (C1 INH), C4b-binding protein (C4bp) and factor H (H).

Figure 3. Inhibition of the MAC of complement by protectin (CD59). By binding to the C5b-8 complex at the C8 chain (a) and C9 (b), CD59 inhibits C9 incorporation and polymerization in the MAC.