Oral Presentation 20th Lancefield International Symposium on Streptococci and Streptococcal Diseases 2017

Not a coiled coil: structural characterization of the hypervariable region of M3 and its role in collagen binding and biofilm (#17)

Ulrich Schwarz-Linek 1 , Conny Yu 1 , Katrin Ackermann 1 , Bela Bode 1 , Richard Farndale 2 , Takeaki Wajima 3 , Anna Norrby-Teglund 3
  1. Biomedical Sciences Research Complex, University of St Andrews, St. Andrews, United Kingdom
  2. Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
  3. Karolinska Institutet, Stockholm, Sweden

The multiple and often serotype-specific functions of M proteins are generally poorly understood in molecular terms, arguably due to a lack of structural information. All available evidence supports the idea of M proteins adopting an elongated dimeric, parallel coiled-coil conformation. This makes M proteins difficult targets for conventional structural biology. We combined EPR and NMR spectroscopy to map the hypervariable region (HVR) in full length M3 protein in solution and derive a structural model. M3-HVR was found to form a well-defined folded structure that deviates from coiled coil topology. This fold presents collagen-binding motifs associated with rheumatic fever in a structural context that depends on the dimeric state of the protein and is required for binding activity. Using triple-helical peptide libraries we identified M3-binding regions within the triple-helical domain of collagen II. The M protein:collagen interaction was found to mediate biofilm formation of M3 clinical isolates.

Our study reveals a surprising structural complexity of the M3 protein with implications for its function in rheumatic fever and biofilms. It also suggests that M proteins may be structurally more diverse than assumed.