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. (2015) © 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., 2012 © 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. (2006) © Nature Publishing Group.)


Bally I, Rossi V, Lunardi T, et al. (2009) Identification of the C1q‐binding sites of human C1r and C1s: a refined three‐dimensional model of the C1 complex of complement. Journal of Biological Chemistry 284: 19340–19348.

Bally I, Ancelet S, Moriscot C, et al. (2013) Expression of recombinant human C1q allows identification of the C1r/C1s binding sites. Proceedings of the National Academy of Sciences of the United States of America 110: 8650–8655.

Beinrohr L, Harmat V, Dobó J, et al. (2007) C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease. Journal of Biological Chemistry 282: 21100–21109.

Bos IG, Hack CE and Abrahams JP (2002) Structural and functional aspects of C1‐inhibitor. Immunobiology 205: 518–533.

Botto M (1998) C1q knock‐out mice for the study of complement deficiency in autoimmune disease. Experimental and Clinical Immunogenetics 15: 231–234.

Budayova‐Spano M, Lacroix M, Thielens NM, et al. (2002) The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex. EMBO Journal 21: 231–239.

Cooper NR (1985) The classical complement pathway: activation and regulation of the first complement component. Advances in Immunology 37: 151–216.

Degn SE, Hansen AG, Steffensen R, et al. (2009) MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. Journal of Immunology 183: 7371–7378.

Degn SE, Jensen L, Hansen AG, et al. (2012) Mannan‐binding lectin‐associated serine protease (MASP)‐1 is crucial for lectin pathway activation in human serum, whereas neither MASP‐1 nor MASP‐3 is required for alternative pathway function. Journal of Immunology 189: 3957–3969.

Dodds AW, Ren XD, Willis AC and Law SKA (1996) The reaction mechanism of the internal thioester in the human complement component C4. Nature 379: 177–179.

van den Elsen JM, Martin A, Wong V, et al. (2002) X‐ray crystal structure of the C4d fragment of human complement component C4. Journal of Molecular Biology 322: 1103–1115.

Feinberg H, Uitdehaag JC, Davies JM, et al. (2003) Crystal structure of the CUB1‐EGF‐CUB2 region of mannose‐binding protein associated serine protease‐2. EMBO Journal 22: 2348–2359.

Gaboriaud C, Rossi V, Bally I, Arlaud GJ and Fontecilla‐Camps JC (2000) Crystal structure of the catalytic domain of human complement C1s: a serine protease with a handle. EMBO Journal 19: 1755–1765.

Gaboriaud C, Juanhuix J, Gruez A, et al. (2003) The crystal structure of the globular head of component protein C1q provides a basis for its versatile recognition properties. Journal of Biological Chemistry 278: 46974–46982.

Gaboriaud C, Thielens NM, Gregory LA, et al. (2004) Structure and activation of the C1 complex of complement: unravelling the puzzle. Trends in Immunology 25: 368–373.

Gaboriaud C, Ling WL, Thielens NM, Bally I and Rossi V (2014) Deciphering the fine details of C1 assembly and activation mechanisms: mission impossible? Frontiers in Immunology 5: 565.

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

Gregory LA, Thielens NM, Arlaud GJ, et al. (2003) X‐ray structure of the Ca2+‐binding interaction domain of C1s. Insights into the assembly of the C1 complex of complement. Journal of Biological Chemistry 278: 32157–32164.

Gregory LA, Thielens NM, Matsushita M, et al. (2004) The X‐ray structure of human mannan‐binding lectin‐associated protein 19 (MAp19) and its interaction site with mannan‐binding lectin and L‐ficolin. Journal of Biological Chemistry 279: 29391–29397.

Harmat V, Gál P, Kardos J, et al. (2004) The structure of MBL‐associated serine protease‐2 reveals that identical substrate specificities of C1s and MASP‐2 are realized through different sets of enzyme‐substrate interactions. Journal of Molecular Biology 342: 1533–1546.

Henriksen ML, Brandt J, Andrieu JP, et al. (2013) Heteromeric complexes of native collectin kidney 1 and collectin liver 1 are found in the circulation with MASPs and activate the complement system. Journal of Immunology 15: 6117–6127.

Inal JM, Hui KM, Miot S, et al. (2005) Complement C2 receptor inhibitor trispanning: a novel human complement inhibitory receptor. Journal of Immunology 174: 256–366.

Janssen BJ, Huizinga EG, Raaijmakers HC, et al. (2005) Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437: 505–511.

Janssen B, Christodoulidou A, McCarthy A, Lambris JD and Gros P (2006) Structure of C3b reveals conformational changes that underlie complement activity. Nature 444: 213–216.

Kidmose RT, Laursen NS, Dobó J, et al. (2012) Structural basis for activation of the complement system by component C4 cleavage. Proceedings of the National Academy of Sciences of the United States of America 109: 15425–15430.

Kjaer TR, Le le TM, Pedersen JS, et al. (2015) Structural insights into the initiating complex of the lectin pathway of complement activation. Structure 23: 342–351.

Krishnan V, Xu Y, Macon K, Volanakis JE and Narayana SV (2007) The crystal structure of C2a, the catalytic fragment of classical pathway C3 and C5 convertase of human complement. Journal of Molecular Biology 367: 224–233.

Krishnan V, Xu Y, Macon K, Volanakis JE and Narayana SV (2009) The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation. Acta Crystallographica Section D 65: 266–274.

Lacroix M, Dumestre‐Pérard C, Schoehn G, et al. (2009) Residue Lys57 in the collagen‐like region of human L‐ficolin and its counterpart Lys47 in H‐ficolin play a key role in the interaction with the mannan‐binding lectin‐associated serine proteases and the collectin receptor calreticulin. Journal of Immunology 182: 456–465.

Matsushita M and Fujita T (2001) Ficolins and the lectin complement pathway. Immunological Reviews 180: 78–85.

Megyeri M, Jani PK, Kajdácsi E, et al. (2014) Serum MASP‐1 in complex with MBL activates endothelial cells. Molecular Immunology 59: 39–45.

Milder FJ, Raaijmakers HC, Vandeputte MD, et al. (2006) Structure of complement component C2a: implications for convertase formation and substrate binding. Structure 14: 1587–1597.

Morgan BP and Walport MJ (1991) Complement deficiency and disease. Immunology Today 12: 301–306.

Munthe‐Fog L, Hummelshoj T, Honoré C, et al. (2009) Immunodeficiency associated with FCN3 mutation and ficolin‐3 deficiency. New England Journal of Medicine 360: 2637–2644.

Nagar B, Jones RG, Diefenbach RJ, Isenman DE and Rini JM (1998) X‐ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Science 280: 1277–1281.

Pflieger D, Przybylski C, Gonnet F, et al. (2010) Analysis of human C1q by combined bottom‐up and top‐down mass spectrometry: detailed mapping of post‐translational modifications and insights into the C1r/C1s binding sites. Molecular and Cellular Proteomics 9: 593–610.

Rooryck C, Diaz‐Font A, Osborn DP, et al. (2011) Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. Nature Genetics 43: 197–203.

Rossi V, Bally I, Ancelet S, et al. (2010) Functional characterization of the recombinant human C1 inhibitor serpin domain: insights into heparin binding. Journal of Immunology 184: 4982–4989.

Ruseva MM, Takahashi M, Fujita T and Pickering MC (2014) C3 dysregulation due to factor H deficiency is mannan‐binding lectin‐associated serine proteases (MASP)‐1 and MASP‐3 independent in vivo. Clinical and Experimental Immunology 176: 84–92.

Schlapbach LJ, Thiel S, Kessler U, et al. (2011) Congenital H‐ficolin deficiency in premature infants with severe necrotising enterocolitis. Gut 60: 1438–1439.

Sekine H, Takahashi M, Iwaki D and Fujita T (2013) The role of MASP‐1/3 in complement activation. Advances in Experimental Medicine and Biology 735: 41–53.

Selander B, Mårtensson U, Weintraub A, et al. (2006) Mannan‐binding lectin activates C3 and the alternative complement pathway without involvement of C2. Journal of Clinical Investigation 116: 1425–1434.

Sirmaci A, Walsh T, Akay H, et al. (2010) MASP1 mutations in patients with facial, umbilical, coccygeal, and auditory findings of Carnevale, Malpuech, OSA, and Michels syndromes. American Journal of Human Genetics 87: 679–686.

Stengaard‐Pedersen K, Thiel S, Gadjeva M, et al. (2003) Inherited deficiency of mannan‐binding lectin‐associated serine protease 2. New England Journal of Medicine 349: 554–560.

Strang CJ, Siegel RC, Phillips ML, Poon PH and Schumaker VN (1982) Ultrastructure of the first component of human complement: electron microscopy of the crosslinked complex. Proceedings of the National Academy of Sciences of the United States of America 79: 586–590.

Teillet F, Gaboriaud C, Lacroix M, et al. (2008) Crystal structure of the CUB1‐EGF‐CUB2 domain of human MASP‐1/3 and identification of its interaction sites with mannan‐binding lectin and ficolins. Journal of Biological Chemistry 283: 25715–25724.

Tenner AJ and Fonseca MI (2006) The double‐edged flower: roles of complement protein C1q in neurodegenerative diseases. Advances in Experimental Medicine and Biology 586: 153–176.

Turner MW (1996) Mannose‐binding lectin: the pluripotent molecule of the innate immune system. Immunology Today 17: 532–540.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
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]