Streptolysin O Accelerates the Conversion of Plasminogen to Plasmin

Tang, D.; Khakzad, H.; Hjortswang, E.; Malmström, L.; Ekström, S.; Happonen, L.; Malmström, J.

doi:10.1101/2024.05.15.594458

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bioRxiv · 10.1101/2024.05.15.594458

Streptolysin O Accelerates the Conversion of Plasminogen to Plasmin

Tang, D.·Khakzad, H.·Hjortswang, E.·Malmström, L.·Ekström, S.·Happonen, L.·Malmström, J.

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Abstract

Streptococcus pyogenes is a human-specific bacterial pathogen that produces several proteins that exploit the plasminogen (PLG)-plasmin (PLM) fibrinolysis system to dismantle blood clots and to facilitate spread and survival within the host. In this study, we explored the interactions between streptolysin O (SLO), a key cytolytic toxin produced by S. pyogenes, and human plasma proteins using affinity-enrichment mass spectrometry. SLO binds specifically to PLG, and this interaction accelerates the conversion of PLG to PLM by tissue-type plasminogen activator (tPA). To further investigate the molecular detail of the PLG-SLO interaction, we employed hydrogen/deuterium exchange mass spectrometry combined with targeted cross-linking mass spectrometry, uncovering that SLO binding induces local conformational shifts in PLG. These changes lead to the formation of a stabilized intermediate PLG-SLO complex that becomes significantly more sensitive to proteolytic processing by tPA. Our findings reveal a conserved moonlighting pathomechanistic role for SLO extending beyond the well characterized cytolytic activity. Additionally, the work underscores the diversity of functional proteomics in identifying and clarifying new host-pathogen interactions.

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Tang, D., Khakzad, H., Hjortswang, E., Malmström, L., Ekström, S., Happonen, L., Malmström, J.. 2024-05-16. Streptolysin O Accelerates the Conversion of Plasminogen to Plasmin. https://doi.org/10.1101/2024.05.15.594458

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