Creation of C4 and C2 activators

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

Two pathways lead to a complex capable of activating C4 and C2.

The classical pathway is triggered by activation of the C1-complex, which consists of hexameric molecule C1q and a tetramer comprising two C1r and two C1s serine proteinases. This occurs when C1q binds to IgM or IgG complexed with antigens, a single IgM can initiate the pathway while multiple IgGs are needed, or when C1q binds directly to the surface of the pathogen. Binding leads to conformational changes in C1q, activating the serine protease activity of C1r, which then cleaves C1s, another serine protease. The C1r:C1s component is now capable of splitting C4 and C2 to produce the classical C3-convertase C4b2a. C1r and C1s are additionally controlled by C1-inhibitor.(Kerr MA 1980)
The lectin pathway is similar in operation but has different components.

Mannose-binding lectin (MBL) or ficolins (L-ficolin, M-ficolin and H-ficolin) initiate the lectin pathway cascade by binding to specific carbohydrate patterns on pathogenic cell surfaces. MBL and ficolins circulate in plasma in complexes with homodimers of MBL-associated serine proteases (MASP) (Fujita et al. 2004; Hajela et al. 2002). Upon binding of human lectin (MBL or ficolins) to the target surface the complex of lectin:MASP undergoes conformational changes, which results in the activation of MASPs by cleavage (Matsushita M et al. 2000; Fujita et al. 2004). Activated MASPs become capable of C4 and C2 cleavage, giving rise to the same C3 convertase C4b:C2a as the classical pathway.

Literature References
PubMed ID Title Journal Year
70787 Cleavage of C2 by C1s into the antigenically distinct fragments C2a and C2b: demonstration of binding of C2b to C4b

Nagasawa, S, Stroud, RM

Proc Natl Acad Sci U S A 1977
11044372 Serine proteases of the complement system

Sim, RB, Laich, A

Biochem Soc Trans 2000
12396008 The biological functions of MBL-associated serine proteases (MASPs)

Hajela, K, Kojima, M, Ambrus, G, Wong, KH, Moffatt, BE, Ferluga, J, Hajela, S, Gal, P, Sim, RB

Immunobiology 2002
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Orthologous Events