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Mapping the Mutational Landscape for Streptokinase Binding to Plasminogen
Srishti Baid1, Matthew L Holding1,2, Taylor Laurin1
1Life Sciences Institute, University of Michigan, Ann Arbor.
Biorxiv : the Preprint Server for Biology
|February 13, 2026
Summary
Group A Streptococcus streptokinase activates human plasminogen, aiding bacterial spread. Deep mutational scanning identified key regions influencing this interaction, crucial for understanding virulence and developing new therapeutics.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Group A Streptococcus (GAS) utilizes streptokinase (SK) to activate human plasminogen (PLG), facilitating bacterial dissemination by degrading fibrin clots.
- This non-enzymatic activation pathway contrasts with the physiological proteolytic activation of PLG to plasmin.
- SK's specificity for human PLG and strain-specific variations are linked to differences in binding affinity and disease severity.
Purpose of the Study:
- To map the functional effects of single amino acid substitutions in streptokinase on human plasminogen binding using deep mutational scanning.
- To identify regions within streptokinase critical for plasminogen interaction and activation.
- To provide a foundation for understanding GAS virulence, human specificity of SK, and potential therapeutic development.
Main Methods:
- Deep mutational scanning (DMS) was applied to streptokinase from Group C Streptococcus, which shares homology with GAS SK.
- Streptokinase was expressed as a fusion protein with the M13 filamentous phage p3 coat protein to facilitate binding assays.
- Phage display systems were used to analyze the binding affinity of mutated SK variants to human plasminogen.
Main Results:
- Approximately 71% of single amino acid substitutions in SK were analyzed for their impact on PLG binding.
- The DMS analysis identified specific regions within SK where mutations significantly alter plasminogen binding affinity.
- Findings suggest a complex protein-protein interaction involving long-range dynamics in the conformational activation of PLG.
Conclusions:
- Deep mutational scanning provides a high-resolution map of streptokinase's functional landscape regarding plasminogen interaction.
- The study elucidates key determinants of streptokinase's human specificity and its role in virulence.
- These findings can inform the development of novel therapeutics targeting streptokinase activity for conditions like heart attack and stroke.
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