A peptide mimicking the C-terminal part of the reactive center loop induces the transition to the latent form of plasminogen activator inhibitor type-1

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of plasminogen activators (uPA and tPA) and thus plays a central role in fibrinolysis. The spontaneous insertion of its reactive centre loop (RCL) into β-sheet A is responsible for its irreversible conversion into the inactive latent form. In this study, we used two peptides mimicking residues P14–P9 and P8–P3 of the RCL so as to understand this dynamic process. We show that both peptides inhibit the formation of PAI-1/uPA and PAI-1/tPA complexes via two different mechanisms. Targeting the N-terminal part of the loop induces the cleavage of PAI-1 by the proteases uPA/tPA while targeting its C-terminal part greatly favors the irreversible formation of latent PAI-1.Structured summary of protein interactionsPAI-1 and uPA bind by comigration in gel electrophoresis (View interaction)tPA and PAI-1bind by comigration in gel electrophoresis (View interaction)

► PAI-1 RCL peptides inhibit the formation of complexes between PAI-1 and uPA/tPA. ► Peptide RCLp14-9 of PAI-1 induces the substrate behavior of the serpin. ► Peptide RCLp8-3 of PAI-1 favors the irreversible formation of latent PAI-1.