Structural similarities and differences in Staphylococcus aureus exfoliative toxins A and B as revealed by their crystal structures

Staphylococcal aureus epidermolytic toxins (ETs) A and B are responsible fo r the induction of staphylococcal scalded skin syndrome, a disease of neona tes and young children. The clinical features of this syndrome vary from lo calized blisters to severe exfoliation affecting most of the body surface. Comparison of the crystal structures of two subtypes of ETs-rETA (at 2.0 An gstrom, resolution), rETB (at 2.8 Angstrom resolution), and an active site variant of rETA, Ser195Ala at 2.0 Angstrom resolution has demonstrated that their overall topology resembles that of a "trypsin-like" serine protease, but with significant differences at the N- and C-termini and loop regions. The details of the catalytic site in both ET structures are very similar t o those in glutamate-specific serine proteases, suggesting a common catalyt ic mechanism. However, the "oxyanion hole," which is part of the catalytic sites of glutamate specific serine proteases, is in the closed or inactive conformation for rETA, yet in the open or active conformation for rETB. The ETs contain a unique amphipathic helix at the N-terminus, and it appears t o be involved in optimizing the conformation of the catalytic site residues . Determination of the structure of the rETA catalytic site variant, Ser195 Ala, showed no significant perturbation at the active site, establishing th at the loss of biological and esterolytic activity can be attributed solely to disruption of the catalytic serine residue. Finally, the crystal struct ure of ETs, together with biochemical data and mutagenesis studies, strongl y confirms the classification of these molecules as "serine proteases" rath er than "superantigens.".