Complement: Classical and Lectin Pathways


The classical and lectin pathways of complement are major recognition systems of innate immunity that are found in mammals and other animal species. By means of several multimolecular proteases, each comprising a recognition protein and a protease component, pathogens and other targets are detected and thereby trigger proteolytic reactions. The classical pathway is initiated by C1, a complex of the recognition molecule C1q and two associated enzymes, C1r and C1s, whereas the lectin pathway is initiated by carbohydrate recognition molecules (mannan‐binding lectin (MBL) or one of the three ficolins or collectin‐LK) in complex with another set of enzymes, MBL‐associated serine proteases (MASPs). Both pathways converge to the formation of C3 convertase, a complex protease that cleaves C3, the central component of the complement system. Proteolytic cleavage of C3 generates a series of fragments and elicits various effector mechanisms, including inflammation and phagocytosis. These mechanisms contribute to the elimination of pathogenic microorganisms and altered host cells from blood and tissues and modulate the adaptive immune response.

Key Concepts

  • C1q, MBL, CL‐LK and ficolins are pattern‐recognition molecules able to sense motifs on pathogens and altered self‐cells.
  • C1q is a major sensor of apoptotic cells and regulator of immune tolerance.
  • Proteolytic cleavage of C3 is pivotal for amplification of the complement response and labelling of the target particles.
  • Target recognition, proteolysis and complex formation generate conformational changes that underlie complement functioning.
  • Complement activation and activity are tightly regulated to avoid noxious side‐effects on normal host cells and tissues.

Keywords: altered self‐cells clearance; innate immunity; inflammation; pathogens; pattern recognition; phagocytosis; proteolysis

Figure 1. Modular structures of the proteins of the classical and lectin pathways. The nomenclature and symbols used for protein modules are the following. 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; LNK, linker module; MG, macroglobulin module; Ser Pr, serine protease domain; TED, thioester‐containing domain; VA, von Willebrand factor type A (VWFA) module. Heterotrimeric associations of gC1q modules (A, B, C) are found at the C‐terminal end of the collagen stems of C1q. Homotrimeric associations of C‐type lectin (carbohydrate recognition domain, CRD) and fibrinogen‐like (FBG) modules are found at the corresponding positions in mannan‐binding lectin or collectin‐LK 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 shown as black triple helices, coiled‐coil structures are in grey and cysteine‐rich regions in black. C1q is a hexamer, whereas mannan‐binding lectin and collectin‐LK are present in serum in multiple oligomeric forms. Ficolin‐2 and ficolin‐1 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, the cleavage shown is that mediated by C3 convertase and for C4 the cleavage site for C1s or MASP‐2 is shown. The N‐terminal end of the α′ chain of C3b and C4b and the location of the internal thioester group of C3 and C4 are indicated. The relative sizes of the proteins are approximate. See also: Multidomain Proteins
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 collectins (MBL or CL‐LK) 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.
Figure 3. Model of the C1 complex of complement: side (a) and bottom (b) views. C1q, C1r and C1s are yellow, red/green and magenta/blue, 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 and C1s lie on the lower part of the cone (Cat on (a), foreground on (b)). They mediate C1 activation. The interaction regions of C1r and C1s mediate the assembly of the C1s–C1r–C1r–C1s tetramer and its interaction with the lysine residues B61 and C58, located in the middle of the C1q stems (Int on (a))
Figure 4. (a) Juxtaposition‐dependent activation and transactivation of MASPs upon MBL binding to a surface. MASP‐1 in a MBL/MASP‐1 complex activates MASP‐2 in a neighbour MBL/MASP‐2 complex. The domains of one of the MASPs are indicated on the figure. (Modified with permission from Kjaer et al. () © Elsevier.) (b) Structure of the C4 · MASP‐2 complex. Except for C4a (red) and the C345C domain (brown), C4 is shown in blue. The MASP‐2 CCP domains (magenta) interact with the C4 C345C domain, whereas the catalytic SP domain (grey) recognises C4 at the scissile bond region. (Modified from Kidmose et al., © Proceedings of the National Academy of Sciences of the USA.)
Figure 5. Crystal structure 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 . The thioester moiety is shown as red spheres. (Modified with permission from Janssen et al. () © Nature Publishing Group.)


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Further Reading

Arlaud GJ, Volanakis JE, Thielens NM, et al. (1998) The atypical serine proteases of the complement system. Advances in Immunology 69: 249–307.

Dodds AW (2002) Which came first, the lectin/classical pathway or the alternative pathway of complement? Immunobiology 205: 340–354.

Fujita T (2002) Evolution of the lectin complement pathway and its role in innate immunity. Nature Reviews Immunology 2: 346–353.

Garlatti V, Martin L, Lacroix M, et al. (2010) Structural insights into the recognition properties of human ficolins. Journal of Innate Immunity 2: 17–23.

Garred P, Honoré C, Ma YJ, et al. (2010) The Genetics of Ficolins. Journal of Innate Immunity 2: 3–16.

Gros P, Milder FJ and Janssen BJ (2008) Complement driven by conformational changes. Nature 8: 48–58.

Holmskov U, Thiel S and Jensenius JC (2003) Collectins and ficolins: humoral lectins of the innate immune defense. Annual Review of Immunology 21: 547–578.

Liszewski MK, Farries TC, Lublin DM, Rooney IA and Atkinson JP (1996) Control of the complement system. Advances in Immunology 61: 201–283.

Ricklin D, Hajishengallis G, Yang K and Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nature Immunology 11: 785–797.

Volanakis JE and Frank MM (eds) (1998) The Human Complement System in Health and Disease. New York: Marcel Dekker.

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Thielens, Nicole M, Gaboriaud, Christine, and Thiel, Steffen(Sep 2015) Complement: Classical and Lectin Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000510.pub4]