Intramolecular general acid catalysis in the binding reactions of alpha 2-macroglobulin and complement components C3 and C4.

The complement system proteins C3 and C4 and the plasma protease inhibitor alpha 2-macroglobulin, when activated by limited proteolysis, can bind covalently to other macromolecules. The three proteins also exhibit an unusual internal peptide-bond cleavage reaction when denatured. The covalent binding reaction is likely to occur by a transacylation mechanism involving an internal thiolester in the three proteins. However, the activated species of these proteins are much more reactive than simple thiolesters. Studies of molecular models of the thiolester region in C3 show that an intramolecular acid catalysis mechanism can both account for the exceptional reactivity of the activated form of these proteins and provide an explanation for the denaturation-induced peptide bond cleavage.