期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1999
卷号：96
期号：16
页码：8879-8883
DOI：10.1073/pnas.96.16.8879
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Plasminogen (Pg) activators such as streptokinase (SK) save lives by generating plasmin to dissolve blood clots. Some believe that the unique ability of SK to activate Pg in the absence of fibrin limits its therapeutic utility. We have found that SK contains an unusual NH2-terminal "catalytic switch" that allows Pg activation through both fibrin-independent and fibrin-dependent mechanisms. Unlike SK, a mutant (rSK{Delta}59) fusion protein lacking the 59 NH2-terminal residues was no longer capable of fibrin-independent Pg activation (kcat/Km decreased by >600-fold). This activity was restored by coincubation with equimolar amounts of the NH2-terminal peptide rSK1-59. Deletion of the NH2 terminus made rSK{Delta}59 a Pg activator that requires fibrin, but not fibrinogen, for efficient catalytic function. The fibrin-dependence of the rSK{Delta}59 activator complex apparently resulted from selective catalytic processing of fibrin-bound Pg substrates in preference to other Pg forms. Consistent with these observations, the presence (rSK) or absence (rSK{Delta}59) of the SK NH2-terminal peptide markedly altered fibrinolysis of human clots suspended in plasma. Like native SK, rSK produced incomplete clot lysis and complete destruction of plasma fibrinogen; in contrast, rSK{Delta}59 produced total clot lysis and minimal fibrinogen degradation. These studies indicate that structural elements in the NH2 terminus are responsible for SK's unique mechanism of fibrin-independent Pg activation. Because deletion of the NH2 terminus alters SK's mechanism of action and targets Pg activation to fibrin, there is the potential to improve SK's therapeutic efficacy.
