ATP-regulated activity of the plasmin-streptokinase complex: a novel mechanism involving phosphorylation of streptokinase.
Streptokinase, an extracellular protein produced by Streptococci, is capable of activating the human fibrinolytic zymogen plasminogen. The rate of amidolytic activity of the plasminogen-streptokinase complex is greatly diminished by micromolar concentrations of ATP and heparin oligosaccharides. In addition, the plasminogen activator activity of the plasminogen-streptokinase complex is also inhibited by these effectors. ATP and heparin oligosaccharides show structural similarity, suggesting that the inhibition is caused by binding of these molecules to a common newly formed binding pocket in streptokinase, which appears after interaction with plasminogen. Addition of the bivalent cations Ca2+ and Mg2+ reverses the inhibition caused by ATP and heparin. In the presence of ATP and bivalent cations, the complex between plasminogen and streptokinase develops an autophosphorylating activity whose target is the sequence LTSRPAHG in the 4.5 kDa streptokinase N-terminal peptide, which is an early autolysis peptide. This streptokinase N-terminal peptide, which is essential for streptokinase activating activity, may serve, once phosphorylated, in mechanisms related to the pathogenicity of Streptococci. These studies suggest a critical role for plasminogen in regulating the activity of the streptokinase molecule.
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
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Serrano
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Rodriguez
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Pizzo
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Gonzalez-Gronow
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology; D004586:Electrophoresis; D004789:Enzyme Activation; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008274:Magnesium / Q000494:pharmacology; D008969:Molecular Sequence Data; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D010960:Plasminogen Activators / Q000378:metabolism / Q000494:pharmacology; D013291:Streptococcus / Q000201:enzymology / Q000502:physiology; D013300:Streptokinase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D010761:Phosphorus Radioisotopes; D000255:Adenosine Triphosphate; D006493:Heparin; D013300:Streptokinase; D010960:Plasminogen Activators; D005341:Fibrinolysin; D008274:Magnesium; D002118:Calcium