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Conserved patterns hidden within group A Streptococcus M protein hypervariability recognize human C4b-binding protein

Cosmo Z Buffalo1, Adrian J Bahn-Suh1, Sophia P Hirakis1

  • 1Department of Chemistry &Biochemistry, University of California, San Diego, La Jolla, California 92093, USA.

Nature Microbiology
|September 6, 2016
PubMed

Insights

A new study reveals how human C4b-binding protein (C4BP) broadly recognizes group A Streptococcus (GAS) M proteins, despite their hypervariability. This discovery offers a potential strategy for developing new GAS therapies and vaccines.

Area of Science:

  • Microbiology
  • Immunology
  • Structural Biology

Background:

  • Group A Streptococcus (GAS) causes significant global morbidity and mortality, with no existing vaccine.
  • The hypervariable M protein, with over 200 types, presents a major obstacle for vaccine development due to narrow antibody protection.
  • GAS utilizes surface-bound C4b-binding protein (C4BP) to evade phagocytic killing.

Purpose of the Study:

  • To elucidate the mechanism by which C4BP recognizes diverse M protein hypervariable regions (HVRs).
  • To explore the potential for targeting the M-C4BP interaction for therapeutic and vaccine development.

Main Methods:

  • Structure determination of four sequence-diverse M proteins in complex with C4BP.
  • Analysis of protein-protein interactions at a molecular level.

Main Results:

  • C4BP interacts with approximately 90% of known M protein HVRs, a rare broad recognition.
  • Structural analysis revealed a conserved 'reading head' mechanism in C4BP that detects conserved sequence patterns within the hypervariable M proteins.
  • This interaction mechanism is distinct from typical antibody recognition of M protein HVRs.

Conclusions:

  • C4BP's broad recognition of GAS M proteins is mediated by a conserved structural motif recognizing hidden conserved sequences.
  • Targeting the M-C4BP interaction presents a promising avenue for developing novel anti-GAS therapies.
  • Understanding this interaction mechanism provides a foundation for designing effective GAS vaccines.

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