THE INTERNAL THIOESTER AND THE COVALENT BINDING-PROPERTIES OF THE COMPLEMENT PROTEINS C3 AND C4

The covalent binding of complement components C3 and C4 is critical fo r their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which in volves a conformational change initiated by the cleavage of a single p eptide bond, the thioester becomes available to react with molecules w ith nucleophilic groups. This description is probably sufficient to ac count for the binding of the C4A isotype of human C4 to amino nucleoph iles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxy l nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbo hydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioest er provides a means to contain this very damaging reaction to the imme diate proximity of the site of activation.