Functional and structural insights of a Staphylococcus aureus apoptotic-like membrane peptide from a toxin-antitoxin module

J Biol Chem. 2012 Dec 21;287(52):43454-63. doi: 10.1074/jbc.M112.402693. Epub 2012 Nov 5.


We report a functional type I toxin-antitoxin (TA) module expressed by a human pathogen, Staphylococcus aureus. TA systems consist of stable toxins and labile antitoxins encoded within small genetic modules widespread in eubacteria and archaea. TA genes provide stress adaptation and protection against DNA loss or invasion. The genes encoding the SprA1 toxic peptide (PepA1) and the SprA1(AS) RNA antitoxin are within a pathogenicity island on opposite strands and possess a 3' overlap. To prevent peptide toxicity during S. aureus growth, PepA1 expression from stable (half-life > 3 h) SprA1 is repressed by elevated amounts of unstable (half-life = ∼10 mn) SprA1(AS). In vivo, PepA1 localizes at the bacterial membrane and triggers S. aureus death. Based on NMR and CD data, its solution structure was solved and is a long bent, interrupted helix. Molecular dynamics simulations indicate that PepA1 compaction and helical content fluctuate in accordance with its cytoplasm or membrane location. When inserted into the S. aureus membrane, the PepA1 conformation switches to a ∼7-nm-long continuous helix, presumably forming pores to alter membrane integrity. PepA1 expression is induced upon acidic and oxidative stresses by reducing SprA1(AS) levels. As an altruistic behavior during infection, some cells may induce the expression of that toxin that would facilitate departure from the host immune cells for spreading.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane* / chemistry
  • Cell Membrane* / genetics
  • Cell Membrane* / metabolism
  • Circular Dichroism
  • Humans
  • Membrane Proteins* / chemistry
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Nuclear Magnetic Resonance, Biomolecular
  • Oxidative Stress / physiology*
  • Peptides* / chemistry
  • Peptides* / genetics
  • Peptides* / metabolism
  • Protein Structure, Secondary
  • Staphylococcus aureus* / chemistry
  • Staphylococcus aureus* / genetics
  • Staphylococcus aureus* / metabolism


  • Membrane Proteins
  • Peptides

Associated data

  • PDB/4B19