The structure of a Staphylococcus aureus leucocidin component (LukF-PV) reveals the fold of the water-soluble species of a family of transmembrane pore-forming toxins

Background: Leucocidins and gamma-hemolysins are bi-component toxins secret ed by Staphylococcus aureus. These toxins activate responses of specific ce lls and form lethal transmembrane pores. Their leucotoxic and hemolytic act ivities involve the sequential binding and the synergistic association of a class S and a class F component, which form hetero-oligomeric complexes. T he components of each protein class are produced as non-associated, water-s oluble proteins that undergo conformational changes and oligomerization aft er recognition of their cell targets. Results: The crystal structure of the monomeric water-soluble form of the F component of Panton-Valentine leucocidin (LukF-PV) has been solved by the multiwavelength anomalous dispersion (MAD) method and refined at 2.0 Angstr om resolution. The core of this three-domain protein is similar to that of alpha-hemolysin, but significant differences occur in regions that may be i nvolved in the mechanism of pore formation. The glycine-rich stem, which un dergoes a major rearrangement in this process, forms an additional domain i n LukF-PV. The fold of this domain is similar to that of the neurotoxins an d cardiotoxins from snake venom. Conclusions: The structure analysis and a multiple sequence alignment of al l toxic components, suggest that LukF-PV represents the fold of any water-s oluble secreted protein in this family of transmembrane pore-forming toxins . The comparison of the structures of LukF-PV and alpha-hemolysin provides some insights into the mechanism of transmembrane pore formation for the bi -component toxins, which may diverge from that of the alpha-hemolysin hepta mer.