Abstact

The bacterial pathogen Streptococcus pyogenes (Strep A) recruits the complement regulator factor H (FH) to its surface using M proteins and FbaA. However, no conserved FH-binding sequence pattern is evident in these proteins. To address this, we determined the structures of M5 protein, M6 protein, and FbaA fragments complexed with FH domains 6 and 7. M5 and M6 proteins formed dimeric alpha-helical coiled coils, as expected, while FbaA formed a monomeric three-helix bundle preceded by a loop. Each Strep A protein had a different FH-binding mode, and distinct FH-binding sequence patterns were constructed for each based on substitution mutagenesis. About half of the known 250 Strep A strains were identified to have FH-binding patterns, with the majority due to FbaA as compared to M or M-like Enn proteins. Our structural and functional elucidation of the mechanism of FH recruitment is applicable to the precise investigation of its role in Strep A virulence.