A KEY step in the elimination of pathogens from the body is the covalent binding of complement proteins C3 and C4 to their surfaces(1-5). Proteolytic activation of these proteins results in a conformational change(6,7), and an internal thioester(8-10) is exposed which reacts with amino or hydroxyl groups on the target surface to form amide or ester bonds, or is hydrolysed(11-15). We report here that the binding of the human C4A isotype involves a direct reaction between amino-nucleophiles and the thioester. A two-step mechanism is used by the C4B isotype. The histidine at position 1,106 (aspartic acid in C4A) first attacks the thioester to form an acyl-imidazole intermediate. The released thiol then acts as a base to catalyse the transfer of the acyl group to amino- and hydroxyl-nucleophiles, including water.