High-resolution cryo-EM analysis of a Streptococcus pyogenes M-protein/human plasminogen complex

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.