Structural mechanisms for the recruitment of factor H by Streptococcus pyogenes

Area of Science:

• Microbiology
• Immunology
• Structural Biology

Background:

• Streptococcus pyogenes (Strep A) evades complement-mediated immunity by recruiting factor H (FH).
• M proteins and FbaA are known FH-binding surface proteins of Strep A.
• No conserved sequence pattern for FH binding has been identified in these proteins.

Purpose of the Study:

• To elucidate the structural mechanisms and sequence patterns of factor H (FH) recruitment by Streptococcus pyogenes (Strep A) surface proteins.
• To investigate the FH-binding modes of M5, M6, and FbaA proteins from Strep A.

Main Methods:

• X-ray crystallography was used to determine the structures of M5, M6, and FbaA fragments complexed with FH domains 6 and 7.
• Substitution mutagenesis was employed to define distinct FH-binding sequence patterns for each protein.

Main Results:

• M5 and M6 proteins adopt dimeric alpha-helical coiled-coil structures, while FbaA forms a monomeric three-helix bundle.
• Each Strep A protein exhibits a unique mode of binding to FH.
• Distinct sequence patterns for FH binding were identified for M5, M6, and FbaA.
• Approximately 50% of known Strep A strains possess identified FH-binding patterns, primarily mediated by FbaA.

Conclusions:

• The study provides structural and functional insights into the mechanism of FH recruitment by Strep A.
• Understanding these distinct binding mechanisms is crucial for investigating the role of FH in Strep A virulence.
• The findings can guide the development of targeted strategies against Strep A infections.