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Updated: Jun 8, 2025
Cryo-EM and Single-Particle Analysis with Scipion
Published on: May 29, 2021
High-resolution cryo-EM analysis of a Streptococcus pyogenes M-protein/human plasminogen complex
Bradley M Readnour1, Sheiny Tjia-Fleck1, Nathan R McCann1
1W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Abstract:
The importance of human plasminogen (hPg)/plasmin (hPm)/cell receptor complexes in invasiveness of cells has been amply established. The objective of this investigation was to determine a high-resolution structure of a major Group A Streptococcus (GAS) bacterial receptor (PAM) for hPg/hPm when bound on a cell surface to its major ligand, hPg. As a model cell surface with endogenous PAM, we employed engineered PAM-expressing lentivirus (LV) particles. We show that the ectodomain of a PAM-type M-Protein (M-Prt), in complex with hPg, is folded through distinct intra- and inter-domain interactions to a more compact form on the cell surface, thus establishing a new paradigm for membrane-bound M-Prt/ligand structures. These studies provide a framework for addressing the need for treatments of GAS disease by providing a molecular platform to solve structures of virulence-determining membrane proteins.
Insights
Group A Streptococcus bacteria use PAM receptors to bind human plasminogen (hPg), aiding cell invasion. This study reveals the compact structure of this complex on cell surfaces, offering targets for new treatments.
Area of Science:
- Microbiology
- Structural Biology
- Biochemistry
Background:
- Cellular invasiveness is crucial for pathogens like Group A Streptococcus (GAS).
- GAS utilizes cell surface receptors to bind human plasminogen (hPg) and human plasmin (hPm), facilitating invasion.
- Understanding the structure of these receptor-ligand complexes is key to developing therapeutics.
Purpose of the Study:
- To determine the high-resolution structure of a Group A Streptococcus (GAS) bacterial receptor (PAM) bound to its ligand, human plasminogen (hPg).
- To investigate the structural conformation of the PAM-type M-Protein (M-Prt) ectodomain when complexed with hPg on a cell surface.
Main Methods:
- Engineered lentivirus (LV) particles expressing PAM as a model cell surface.
- High-resolution structural analysis of the M-Prt ectodomain in complex with hPg.
Main Results:
- The M-Prt ectodomain, when bound to hPg on the cell surface, adopts a more compact folded structure.
- Distinct intra- and inter-domain interactions stabilize this compact conformation.
- This reveals a new structural paradigm for membrane-bound M-Prt/ligand complexes.
Conclusions:
- The structural insights into the GAS PAM-hPg complex provide a molecular framework for understanding virulence.
- This work lays the foundation for developing novel therapeutic strategies against GAS infections.
- Targeting these virulence-determining membrane proteins offers a promising avenue for treatment development.
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