Figure 1.

Overview of Classical and Lectin Pathway activation, regulation by C1-INH and proposed mechanism of complex formation. Middle panel: Activation of the classical and the lectin pathway (1). Recognition of triggering compound by the respective recognition molecules (C1q for classical pathway; MBL, ficolins or collectins for lectin pathway) and binding thereof to the activating compounds/structures. (2) Zymogen autoactivation of the first serine protease after structural changes of the associated recognition molecules upon binding to activating structures. (3) Catalytically activation of the second serine proteases by the activated first serine proteases. (4) Cleavage of C2 and C4 by activated serine proteases. (5) Formation of the classical C3 convertase, consisting of C4b and C2b [updated nomenclature according to (3)]. (6) Downstream complement activation going along with the release of several complement activation/split products. (7) Formation of the Terminal Complement Complex (TCC) or the Membrane Attack Complex (MAC complex), when formed on a membrane, and lysis or cell clearance. Left and right panel: Regulation of classical and lectin pathway activation by C1-INH and proposed theory of complex formation. (A) Binding of the pattern recognition molecule to an activating surface, resulting in conformational changes in the respective protein complexes. (B) Activation of serine proteases, allowing downstream complement activation. (C) Regulation of pathway activation by C1-INH through covalent binding to active sites of the serine proteases, blocking protease function and further activation of the respective pathways. (D) Dissociation of the complexes upon binding of C1-INH and release of C1-INH complexes as well as free pattern recognition molecules into the circulation. The figure was created with BioRender.com.