![]() This finding suggests that the native hPg conformation encloses PAM-binding exosites or sterically hinders access to K2 hPg. However, the attendant conformational change upon inactivation of K4 hPg LBS increased the affinity of hPg for PAM by an order of magnitude. In the current study, selective inactivation of the LBS of K1 hPg, K4 hPg, and K5 hPg revealed that the LBS of these kringle domains are dispensable for hPg binding to PAM. Moreover, we sought to establish the significance of the intramolecular interaction between Asp 219 of the LBS of K2 hPg and its serine protease domain binding partner, Lys 708, to conformational changes in hPg. However, these studies did not eliminate any modulatory effects of the non-K2 hPg LBS on this interaction. Recently, we showed, using full-length hPg, that K2 hPg is critical for PAM binding. ![]() Many studies have demonstrated the singular importance of the kringle-2 domain of hPg (K2 hPg) to PAM-binding using hPg fragments. Consequently, GAS enhances virulence by digesting extracellular and tight cellular junctional barriers using hPm activity. In this manner, pattern D skin-trophic strains of Group A streptococci (GAS), through the expression of surface plasminogen-binding M-protein (PAM), immobilize surface hPg, thereby enabling rapid hPg activation by GAS-secreted streptokinase (SK). 2Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, United StatesĪccelerated activation of the human plasminogen zymogen (hPg) to two-chain active plasmin (hPm) is achieved following conformational changes induced by ligand-binding at the lysine-binding sites (LBSs) in four of the five hPg kringle domains.Keck Center for Transgene Research, Notre Dame, IN, United States
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