Key Concepts:

Figure 1. Modular structures of the proteins of the classical and lectin pathways. The nomenclature and symbols used for protein modules are those defined by Bork and Bairoch (1995). ANA, anaphylatoxin; CP, complement control protein (CCP) module; CUB, module found in complement C1r/C1s, Uegf and bone morphogenetic protein; C345C, complement proteins C3/C4/C5 C-terminal module; EG, epidermal growth factor (EGF)-like module; FM, factor I/membrane attack complex proteins C6/C7 (FIMAC) module; LA, low-density lipoprotein receptor class A (LDLRA) module; LNK, linker module; MG, macroglobulin module; SR, scavenger receptor cysteine-rich (SRCR) module; Ser Pr, serine protease domain; TED, thioester-containing domain; VA, von Willebrand factor type A module. Heterotrimeric associations of gC1q modules (A, B and C) are found at the C-terminal end of the collagen stems of C1q. Homotrimeric associations of C-type lectin (CLECT) and fibrinogen-like (FBG) modules are found at the corresponding positions in mannan-binding lectin and the ficolins, respectively. Unlabelled portions of the molecules represent connecting segments or sequence areas with no known homology to other proteins. Areas of collagen-like structure are grey, and coiled-coil structures are shown in black. C1q is a hexamer, whereas mannan-binding lectin is present in serum under multiple oligomeric forms. L-Ficolin and M-ficolin are thought to be mainly tetramers, whereas H-ficolin forms higher oligomers. Arrows indicate peptide bonds cleaved on activation of proteolytic enzymes. In the case of C3 and C4, the only cleavage shown is that mediated by C3 convertase and C1s or MASP-2, respectively. The location of the internal thioester group of C3 and C4 is indicated. The relative sizes of the proteins are approximate.

Figure 2. Classical and lectin pathways of complement. Activation of the classical pathway is triggered by direct or antibody-dependent recognition of a microorganism by C1q, whereas the lectin pathway is initiated by interaction of mannan-binding lectin (MBL) or ficolins with arrays of carbohydrates at the surface of a microorganism. Proteins expressing proteolytic activity are shown in red and proteolytic cleavages are indicated by red arrows. Fragments C4b and C3b exhibiting a reactive thioester group are green, whereas small fragments generating inflammatory reactions are yellow. C1 inhibitor (C1 INH), a member of the serine protease inhibitor (serpin) family, controls both C1 activation and C1 proteolytic activity. Its reactivity towards MASP-1 and MASP-2 is also established. Factor I cleaves C4b and C3b, preventing formation of the convertases and generating C3b fragments endowed with important biological activities.

Figure 3. Crystal structure of the C1r catalytic domain in its resting zymogen state. The domain associates as a head-to-tail homodimer through interactions between the CCP1 module of one molecule and the serine protease (SP) domain of its counterpart. The residues at the catalytic sites (a.s.) and at the cleavage sites are shown. N_A, N_B and C_A, C_B indicate the N- and C-terminal ends of molecules A and B. Modified from Budayova-Spano et al. (2002).

Figure 4. C1 complex of complement. C1q, C1r and C1s are blue, red and green, respectively. Upon assembly of the complex, the extended C1s–C1r–C1r–C1s tetramer is supposed to fold into a compact structure entirely located inside the cone defined by the C1q stems. The catalytic regions of C1r (red) and C1s (dark green) responsible for C1 activation and proteolytic activity towards C4 and C2 lie on the lower part of the cone. The interaction regions of C1r (orange) and C1s (light green) mediate assembly of the C1s–C1r–C1r–C1s tetramer and its interaction with reactive lysine residues in the middle part of the C1q stems. Modified from Bally et al. (2009).

Figure 5. Crystal structures of human C3 and C3b. The structures are shown in ribbon representation. The colour coding and abbreviations for each C3 domain are the same as in Figure 1. The thioester moiety is shown as red spheres. Modified from Janssen et al. (2006) with permission from Nature Publishing Group.