Coiled-coil irregularities and instabilities in group A Streptococcus M1 are required for virulence

Science. 2008 Mar 7;319(5868):1405-8. doi: 10.1126/science.1154470.

Abstract

Antigenically variable M proteins are major virulence factors and immunogens of the human pathogen group A Streptococcus (GAS). Here, we report the approximately 3 angstrom resolution structure of a GAS M1 fragment containing the regions responsible for eliciting type-specific, protective immunity and for binding fibrinogen, which promotes M1 proinflammatory and antiphagocytic functions. The structure revealed substantial irregularities and instabilities throughout the coiled coil of the M1 fragment. Similar structural irregularities occur in myosin and tropomyosin, explaining the patterns of cross-reactivity seen in autoimmune sequelae of GAS infection. Sequence idealization of a large segment of the M1 coiled coil enhanced stability but diminished fibrinogen binding, proinflammatory effects, and antibody cross-reactivity, whereas it left protective immunogenicity undiminished. Idealized M proteins appear to have promise as vaccine immunogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Antibodies, Bacterial / immunology
  • Antigens, Bacterial / chemistry*
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / immunology
  • Antigens, Bacterial / metabolism
  • Bacterial Outer Membrane Proteins / chemistry*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / immunology
  • Bacterial Outer Membrane Proteins / metabolism
  • Carrier Proteins / chemistry*
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism
  • Circular Dichroism
  • Cross Reactions
  • Crystallography, X-Ray
  • Dimerization
  • Fibrinogen / metabolism
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Protein Conformation
  • Protein Structure, Secondary
  • Repetitive Sequences, Amino Acid
  • Streptococcal Infections / immunology
  • Streptococcal Infections / microbiology
  • Streptococcus pyogenes / chemistry*
  • Streptococcus pyogenes / immunology
  • Streptococcus pyogenes / pathogenicity*
  • Virulence

Substances

  • Antibodies, Bacterial
  • Antigens, Bacterial
  • Bacterial Outer Membrane Proteins
  • Carrier Proteins
  • Mutant Proteins
  • streptococcal M protein
  • Fibrinogen

Associated data

  • PDB/2OTO