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Protein Engineering, Vol. 15, No. 9, 753-761, September 2002
© 2002 Oxford University Press

Effects of deletion of streptokinase residues 48–59 on plasminogen activation

N. Wakeham1, S. Terzyan1, P. Zhai1, J.A. Loy2,3, J. Tang2 and X.C. Zhang1,4

1 Crystallography Research Program and 2 Protein Studies Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street,Oklahoma City, OK 73104, USA

Streptokinase (SK) is a thrombolytic agent widely used for the clinical treatment of clotting disorders such as heart attack. The treatment is based on the ability of SK to bind plasminogen (Pg) or plasmin (Pm), forming complexes that proteolytically activate other Pg molecules to Pm, which carries out fibrinolysis. SK contains three major domains. The N-terminal domain, SK{alpha}, provides the complex with substrate recognition towards Pg. SK{alpha} contains a unique mobile loop, residues 45–70, absent in the corresponding domains of other bacterial Pg activators. To study the roles of this loop, we deleted 12 residues in this loop in both full-length SK and the SK{alpha} fragment. Kinetic data indicate that this loop participates in the recognition of substrate Pg, but does not function in the active site formation in the activator complex. Two crystal structures of the deletion mutant of SK{alpha} (SK{alpha}{Delta}) complexed with the protease domain of Pg were determined. While the structure of SK{alpha}{Delta} is essentially the same as this domain in full-length SK, the mode of SK–Pg interaction was however different from a previously observed structure. Even though mutagenesis studies indicated that the current complex represents a minor interacting form in solution, the binding to SK{alpha}{Delta} triggered similar conformational changes in the Pg active site in both crystal forms.


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 J. Biol. Chem.Home page
R. R. Bean, I. M. Verhamme, and P. E. Bock
Role of the Streptokinase {alpha}-Domain in the Interactions of Streptokinase with Plasminogen and Plasmin
J. Biol. Chem., March 4, 2005; 280(9): 7504 - 7510.
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