The reaction mechanism of the internal thioester in the human complement component C4

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.