Mutation of lysines in a plasminogen binding region of streptokinase identifies residues important for generating a functional activator complex

Biochemistry
L F LinG L Reed

Abstract

Through a unique but poorly understood mechanism, streptokinase (SK) interacts with human plasminogen to generate an "activator complex" that efficiently cleaves substrate plasminogen molecules. Previous studies have suggested that lysine residues in SK may play a role in the binding and function of the activator complex. To investigate this hypothesis, 10 different lysine residues in the plasminogen binding region of SK were altered to construct 8 recombinant (r) SK mutants. Only one double mutant, rSKK256,257A (replacing Lys with Ala at residues 256 and 257), showed a statistically significant reduction (63%) in binding affinity for Glu-plasminogen. This mutant also displayed a lagtime in the appearance of maximal activity, and modest impairments (2-5-fold) in kinetic parameters for amidolytic and plasminogen activator activity compared to rSK. In contrast, another mutant, rSKK332,334A, formed an activator complex with profound and nearly selective defects in the catalytic processing of substrate plasminogen molecules. When compared to rSK in kinetic assays of plasminogen activation, the rSKK332,334A mutant formed an activator complex that bound substrate plasminogens normally (normal K(m), but its ability to activate or clea...Continue Reading

References

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Citations

Oct 29, 1998·Protein Science : a Publication of the Protein Society·F Conejero-LaraC P Ponting
Dec 30, 2004·The Journal of Biological Chemistry·Ronald R BeanPaul E Bock
Jul 25, 2003·Proceedings of the National Academy of Sciences of the United States of America·Inna P GladyshevaGuy L Reed
Aug 4, 1999·Proceedings of the National Academy of Sciences of the United States of America·G L ReedL Hedstrom
Oct 6, 1999·FEBS Letters·X WangX C Zhang
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Jun 25, 2004·The Journal of Biological Chemistry·Paul D BoxrudPaul E Bock
Oct 10, 2018·Applied Microbiology and Biotechnology· AdivitiyaYogender Pal Khasa
Jul 31, 2019·Computational and Structural Biotechnology Journal·Jan MicanJiri Damborsky
Oct 23, 2018·Journal of the American Chemical Society·Purba MukherjeeM Reza Ghadiri

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