Nonproteolytic induction of catalytic activity into the single-chain form of urokinase-type plasminogen activator by dipeptides.
2009
Serine proteases are initially synthesized as single-chain proenzymes with activities that are many orders of magnitude lower than those of the mature enzyme. Proteolytic cleavage of an exposed loop liberates a new amino terminus that inserts into a hydrophobic pocket and forms a stabilizing salt bridge with a ubiquitously conserved aspartate residue, resulting in a conformational change organizing the mature oxyanion hole. In a decisive 1976 work, Huber and Bode [Bode, W., and Huber, R. (1976) FEBS Lett. 68, 231−236] demonstrated that peptides sequentially similar to the new amino terminus in combination with a catalytic site inhibitor could specifically induce a trypsin-like conformation in trypsinogen. We now demonstrate that an Ile-Ile or Ile-Val dipeptide can induce limited enzyme activity in the single-chain zymogen form of urokinase-type plasminogen activator (uPA) or its K158A variant, which cannot be activated proteolytically. Furthermore, the slow formation of a covalent serpin−protease complex ...
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