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Plasminogen Activation by Streptokinase via a Unique Mechanism

1998; Elsevier BV; Volume: 273; Issue: 5 Linguagem: Inglês

10.1074/jbc.273.5.3110

1083-351X

Kung Chia Young, Guey-Yueh Shi, Dung-Ho Wu, Li-Ching Chang, Bi Chang, Chung-Pei Ou, Hua-Lin Wu,

Calpain Protease Function and Regulation

The mechanism of human plasminogen (HPlg) activation by streptokinase (SK)-type activator was investigated with recombinant truncated SK peptides. An enzyme-substrate intermediate of HPlg·SK·HPlg ternary complex was demonstrated by a sandwich-binding experiment. Formation of the ternary complex was saturable, HPlg-specific, and inhibited by 6-aminocaproic acid. Three interaction sites between SK and HPlg were demonstrated. SK-(220–414) bound to HPlg with two binding sites: one to the micro-HPlg region, the catalytic domain of HPlg, and one to the kringle 1–5 region, with K d values of 1.50 × 10 −7 and 2.44 × 10 −6 m, respectively. SK-(16–251) bound to a single site on the kringle 1–5 region of HPlg with a K d of 4.09 × 10 −7 m. SK-(220–414) and SK-(16–251) competed for binding on the same or nearby location on the human kringle 1–5 domain. Combination of SK-(220–414) and SK-(16–251), but not either peptide alone, could effectively activate HPlg. In addition, SK-(16–251) dose-dependently enhanced the activation of HPlg by SK-(16–414), while the HPlg activation by SK-(16–414) was inhibited by SK-(220–414). We conclude that the HPlg that binds to the COOH-terminal domains of SK functions as an enzyme to catalyze the conversion of substrate HPlg that binds to the NH 2 -terminal domain of SK to human plasmin.