Streptolysin O accelerates the conversion of plasminogen to plasmin

• Published in: Nature communications 2024-11, Vol.15 (1), p.10212-15, Article 10212
• Main Authors: Tang, Di, Khakzad, Hamed, Hjortswang, Elisabeth, Malmström, Lars, Ekström, Simon, Happonen, Lotta, Malmström, Johan
• Format: Article
• Language: English
• Subjects: 631/1647/296; 631/326/421; 631/45/475/2290; 631/535/1267; 631/57/2272/1590; 82/58; Bacteria; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Bats; Biochemistry and Molecular Biology; Biokemi och molekylärbiologi; Biologi; Biological Sciences; Blood; Blood clots; Blood coagulation; Clinical Medicine; Cytolytic activity; Dismantling; Fibrin; Fibrinolysin - metabolism; Fibrinolysis; Host-Pathogen Interactions; Humanities and Social Sciences; Humans; Infectious Medicine; Infektionsmedicin; Klinisk medicin; Life Sciences; Mass Spectrometry; Mass spectroscopy; Medical and Health Sciences; Medicin och hälsovetenskap; multidisciplinary; Natural Sciences; Naturvetenskap; Pathogens; Plasmin; Plasminogen; Plasminogen - chemistry; Plasminogen - metabolism; Protein Binding; Protein interaction; Proteins; Proteolysis; Science; Science (multidisciplinary); Scientific imaging; Streptococcus; Streptococcus infections; Streptococcus pyogenes - metabolism; Streptokinase; Streptokinase - chemistry; Streptokinase - metabolism; Streptolysins - chemistry; Streptolysins - metabolism; Structural Biology; Strukturbiologi; Tissue Plasminogen Activator - chemistry; Tissue Plasminogen Activator - metabolism; Toxins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54173-6

Group A Streptococcus (GAS) is a human-specific bacterial pathogen that can exploit the plasminogen-plasmin fibrinolysis system to dismantle blood clots and facilitate its spread and survival within the human host. In this study, we use affinity-enrichment mass spectrometry to decipher the host-pathogen protein-protein interaction between plasminogen and streptolysin O, a key cytolytic toxin produced by GAS. This interaction accelerates the conversion of plasminogen to plasmin by both the host tissue-type plasminogen activator and streptokinase, a bacterial plasminogen activator secreted by GAS. Integrative structural mass spectrometry analysis shows that the interaction induces local conformational shifts in plasminogen. These changes lead to the formation of a stabilised intermediate plasminogen-streptolysin O complex that becomes significantly more susceptible to proteolytic processing by plasminogen activators. Our findings reveal a conserved and moonlighting pathomechanistic function for streptolysin O that extends beyond its well-characterised cytolytic activity. Group A Streptococcus exploits the human fibrinolytic system to promote infection. Here, the authors reveal that the bacterial toxin streptolysin O binds to plasminogen and accelerates its conversion to plasmin, thereby dismantling blood clots and facilitating the spread within the human host.