An M protein coiled coil unfurls and exposes its hydrophobic core to capture LL-37

Area of Science:

• Microbiology
• Structural Biology
• Immunology

Background:

• Surface-associated M proteins from Streptococcus pyogenes (Strep A) evade host immunity by interacting with human proteins.
• The mechanism by which M proteins, particularly their coiled-coil structures, achieve specific binding and neutralization of targets like the antimicrobial peptide LL-37 remains unclear.

Purpose of the Study:

• To elucidate the structural basis for the interaction between Streptococcus pyogenes M87 protein and the human antimicrobial peptide LL-37.
• To understand the mechanism of LL-37 neutralization by M proteins and its implications for bacterial immune evasion.

Main Methods:

• X-ray crystallography was employed to determine the structure of the LL-37/M87 protein complex.
• Solution-based assays were used to investigate LL-37 recruitment by M87 protein.
• Genetic analysis of an M87 Strep A strain was performed to assess the in vivo contribution of the identified interaction to LL-37 resistance.

Main Results:

• The crystal structure revealed a novel interaction mode where the M87 coiled coil unfurled, exposing its hydrophobic core to bind LL-37.
• In solution, M87 protein recruited multiple LL-37 molecules, suggesting a 'protein trap' neutralization mechanism.
• The identified interaction mechanism was confirmed to significantly contribute to LL-37 resistance in an M87 Strep A strain and is conserved across prevalent M protein types.

Conclusions:

• Streptococcus pyogenes M87 protein employs a unique structural mechanism, involving coiled-coil unfurling, to neutralize the antimicrobial peptide LL-37.
• This 'protein trap' mechanism is crucial for bacterial survival and immune evasion and is conserved in other M protein variants.
• The findings provide a structural basis for developing therapeutic strategies to inhibit M protein-mediated LL-37 neutralization.