THE STRUCTURE OF STAPHYLOCOCCUS-AUREUS EPIDERMOLYTIC TOXIN-A, AN ATYPIC SERINE-PROTEASE, AT 1.7 ANGSTROM RESOLUTION

Background: Staphylococcal epidermolytic toxins A and B (ETA and ETB) are responsible for the staphylococcal scalded skin syndrome of newbor n and young infants; this condition can appear just a few hours after birth, These toxins cause the disorganization and disruption of the re gion between the stratum spinosum and the stratum granulosum -two of t he three cellular layers constituting the epidermis, The physiological substrate of ETA is not known and, consequently, its mode of action i n vivo remains an unanswered question, Determination of the structure of ETA and its comparison with other serine proteases may reveal insig hts into ETA's catalytic mechanism. Results: The crystal structure of staphylococcal ETA has been determined by multiple isomorphous replace ment and refined al 1.7 Angstrom resolution with a crystallographic R factor of 0.184. The structure of ETA reveals it to be a new and uniqu e member of the trypsin-like serine protease family, In contrast to ot her serine protease folds, ETA can be characterized by ETA-specific su rface loops, a lack of cysteine bridges, an oxyanion hole which is not preformed, an S1 specific pocket designed for a negatively charged am ino acid and an ETA-specific N-terminal helix which is shown to be cru cial for substrate hydrolysis.Conclusions: Despite very low sequence h omology between ETA and other trypsin-like serine proteases, the ETA c rystal structure, together with biochemical data and site-directed mut agenesis studies, strongly confirms the classification of ETA in the G lu-endopeptidase family, Direct links can be made between the protease architecture of ETA and its biological activity.