No vaccine exists against group A Streptococcus (GAS), a leading cause of worldwide morbidity and mortality. A severe hurdle is the hypervariability of its major antigen, the M protein, with >200 different M types known. Neutralizing antibodies typically recognize M protein hypervariable regions (HVRs) and confer narrow protection. In stark contrast, human C4b-binding protein (C4BP), which is recruited to the GAS surface to block phagocytic killing, interacts with a remarkably large number of M protein HVRs (apparently ∼90%). Such broad recognition is rare, and we discovered a unique mechanism for this through the structure determination of four sequence-diverse M proteins in complexes with C4BP. The structures revealed a uniform and tolerant ‘reading head’ in C4BP, which detected conserved sequence patterns hidden within hypervariability. Our results open up possibilities for rational therapies that target the M–C4BP interaction, and also inform a path towards vaccine design.
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We thank O. Ghosh for help on the project. This works was supported by National Institutes of Health (NIH) grant T32 GM007240 (C.Z.B.), American Heart Association Predoctoral Fellowship 14PRE18320032 (C.Z.B.), NIH R01 AI096837 (P.G. and V.N.) and NIH R01 AI077780 (V.N.). The work was also funded in part by the National Biomedical Computation Resource, NIH P41 GM103426, NIH Director's New Innovator Award Program DP2-OD007237 and through the National Science Foundation XSEDE Supercomputer Resources Grant RAC CHE060073N to R.E.A. S.P.H. was supported by the Interfaces Multi-Scale Analysis of Biological Structure and Function training grant NIH T32 EB009380.
The authors declare no competing financial interests.
Supplementary Tables 1–3, Supplementary Figures 1–16, legends for Supplementary Videos 1–5, Supplementary References (PDF 10446 kb)
R39 nook in M2-C4BPα1-2. (MOV 9313 kb)
R39 nook in M2 (F75A)-C4BPα1-2. (MOV 9328 kb)
C4BPα2 contacts in M2-C4BPα1-2. (MOV 13863 kb)
C4BPα2 contacts in M2 (K65A)-C4BPα1-2. (MOV 13986 kb)
C4BPα2 contacts in M2 (N66D)-C4BPα1-2. (MOV 13809 kb)
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Buffalo, C., Bahn-Suh, A., Hirakis, S. et al. Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein. Nat Microbiol 1, 16155 (2016). https://doi.org/10.1038/nmicrobiol.2016.155
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