Key Concepts:

Figure 1. Complement activation pathways. The components of complement system can be organised into three major pathways: The classical pathway is mainly initiated by the binding of C1q to antigen–antibody complexes, whereas the lectin pathway is triggered by binding of mannose‐binding lectin (MBL) or ficolins to glycosylated surfaces on microbial cell walls. Both pathways lead to the formation of a common C3 convertase, an enzyme complex with serine proteinase trypsin‐like specificity. The alternative pathway, on the other hand, can be triggered by spontaneous hydrolysis of the internal thioester bond of C3, leading to the formation of . This nonproteolytically activated form of C3 can lead to the formation of the alternative pathway C3 convertase by interacting with factors B and D. This convertase formation can be further induced and stabilised by properdin. C3 convertases generated by all pathways are able to cleave C3 into C3a and C3b, latter of which forms additional convertases, thereby rapidly amplifying complement response. C3b is vitally contributing to the clearance of pathogens by phagocytes (macrophages and neutrophils) and is a major component of the C5 convertase, which in turn cleaves C5 to C5a and C5b. The anaphylatoxins C3a and C5a mediate the inflammatory responses of complement. C5b subsequently takes the lead in formation of the terminal C5b–9 complement complex (TCC), ultimately resulting into cell lysis. Potential roles in the proteolytic activation of C3 and C5 have also been assigned to noncomplement proteinases, including enzymes of the coagulation and fibrinolysis cascades. Reproduced with permission from Springer Science+Business Media: Oikonomopoulou et al., 2012; Figure 1.

Figure 2. Proteolytic and nonproteolytic activation of C3. Native C3 is proteolytically activated by C3 convertase. Nonproteolytic activation can also occur by hydrolysis of the protected, unreactive thioester bond of native C3. The hydrolysis induces a conformational change that allows factor B to bind and form the alternative complement activation pathway C3 convertase (amplification loop is represented by the bold dotted arrow). Cleavage of native C3 by the C3 convertase results in the release of the C3a anaphylatoxin. The resulting conformational change of the remaining C3b molecule allows the thioester bond to react with target surfaces (e.g. microbes, biomaterials, apoptotic cells), leading to opsonisation or lysis of the targets. Dotted black lines within the C3 and C3‐derived molecules indicate the presence of disulfide bonds.