Mechanism and Catalytic Site Atlas

C3/C5 convertase is part of the complement system which is a major defence system in blood plasma against pathogens. The pathway activates the proteases C3 and C5 convertase which cleave proteins C3 and C5 respectively so that the cleaved products can attract phagocytes to the site of infection and tags target cells for elimination by phagocytosis. Also C5 convertase initiates the terminal phase of the complement system, leading to the assembly of the membrane attack complex (MAC). The membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and death.

Both C3 and C5 convertase are made up of the subunits, C2a and C4b. However, C5 convertase in addition to these subunits also has the cleaved product of C3 convertase, C3b, which enables C5 convertase to cleave C5 components. The catalytic subunit of the convertase is C2a which displays the classic serine protease catalytic triad of serine, histidine and aspartate which are key for the mechanism of hydrolysis of peptide bonds with this convertase being specific to Arg-Ser bonds.

Interestingly both C3b and C4b subunits contain a specific binding component on their alpha-chain, a thiolacetone ring, made up of the residues -Cys-Gly-Glu-Gln- which can react with hydroxyl or amino groups and enable the binding of this subunit to other molecules, including membranes and other protein subunits. The thiolacetone ring is usually buried in the protein however after cleavage of the alpha-chain by a protease it is exposed and so is liable to attack by nucleophiles such as hydroxyl and amino groups. Both the C4b and C3b subunit of C3/C5 convertases serve as a platform for the assembly of the proteolytically active convertases that mediate downstream activation of the complement system by cleavage of C3 and C5.