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Structural basis for collagen recognition by the Streptococcus pyogenes M3 protein and its involvement in biofilm

Marta Wojnowska1, Takeaki Wajima2, Tamas Yelland3

  • 1School of Biology, Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews, United Kingdom.

Elife
|December 22, 2025
PubMed

Insights

The M3 protein of group A streptococcus (GAS) binds human collagen, revealing a novel T-shaped structure. This interaction enhances GAS biofilm formation, crucial for invasive infections and vaccine development.

Area of Science:

  • Microbiology
  • Structural Biology
  • Pathogenesis

Background:

  • Streptococcus pyogenes (group A streptococcus, GAS) is a major human pathogen.
  • M protein is a key GAS virulence factor, essential for pathogenesis and vaccine targets.
  • The M3 protein from emm3 GAS is linked to severe invasive diseases.

Purpose of the Study:

  • To structurally and biochemically characterize the interaction between the M3 protein and human collagens.
  • To elucidate the molecular mechanisms underlying emm3 GAS colonization and virulence.
  • To explore therapeutic strategies targeting the M3-collagen interaction and GAS biofilm formation.

Main Methods:

  • X-ray crystallography to determine high-resolution structures of the M3 N-terminal domain and its complex with a collagen peptide.
  • Biochemical assays to characterize the M3-collagen interaction.
  • Biofilm formation assays with emm3 GAS and inhibition studies using recombinant M3 domain.
  • Analysis of tissue biopsies and organotypic skin models to visualize GAS-collagen colocalization.

Main Results:

  • A novel T-shaped protein fold for the M3 N-terminal domain was revealed, with binding sites complementary to collagen triple helices.
  • The M3-collagen interaction facilitates colonization by emm3 GAS and related streptococci.
  • M3-collagen interaction significantly enhances emm3 GAS biofilm formation in an emm type-specific manner.
  • Recombinant N-terminal M3 domain inhibits M3-collagen-mediated biofilm formation.
  • emm3 GAS colocalizes with collagen in patient tissue biopsies and infected skin models, particularly within biofilms.

Conclusions:

  • Detailed molecular insights into the M3-collagen interaction as a significant streptococcal virulence mechanism.
  • The findings have implications for understanding invasive streptococcal infections and biofilm development.
  • Targeting the M3-collagen interaction offers potential for novel therapeutic strategies and M-protein-based vaccine design.
Keywords:
E. coliS. pyogenesbacterial adhesionbiofilmcollagenhumaninfectious diseasemicrobiologymolecular biophysicsprotein structurestreptococcal M proteinsstructural biology

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