Understanding the mechanism of action of the exfoliative toxins of Staphylococcus aureus.
The exfoliative toxins of Staphylococcus aureus are responsible for the staphylococcal scalded skin syndrome, a blistering skin disorder that particularly affects infants and young children, as well as adults with underlying disease. Their three-dimensional structure is similar to other glutamate-specific trypsin-like serine proteases with two substrate-binding domains and a serine-histidine-aspartate catalytic triad that forms the active site. However, unlike other serine proteases, the exfoliative toxins possess a highly charged N-terminal alpha-helix and a unique orientation of a critical peptide bond, which blocks the active site of the toxins so that, in their native state, they do not possess any significant enzymatic activity. The target for the toxins has recently been identified as desmoglein-1, a desmosomal glycoprotein which plays an important role in maintaining cell-to-cell adhesion in the superficial epidermis. It is speculated that binding of the N-terminal alpha-helix to desmoglein-1 results in a conformation change that opens the active site of the toxin to cleave the extracellular domain of desmoglein-1 between the third and fourth domains, resulting in disruption of intercellular adhesion and formation of superficial blisters. Elucidating the mechanism of action of the toxins and identifying desmoglein-1 as their specific epidermal substrate has not only given us an insight into the pathogenesis of the staphylococcal scalded skin syndrome, but also provided us with useful information on normal skin physiology and the pathogenesis of other toxin-mediated diseases. It is hoped that this knowledge will lead to development of rapid screening and diagnostic tests, and new antitoxin strategies for the treatment and prevention of the staphylococcal scalded skin syndrome in the near future.
Ladhani
Shamez
S
Department of Paediatrics, Newham General Hospital, Glen Road, E13 8RU, London, UK. drshamez@aol.com
D000818:Animals; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism; D002648:Child; D051183:Desmoglein 1; D005083:Exfoliatins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007223:Infant; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000378:metabolism / Q000633:toxicity; D013206:Staphylococcal Scalded Skin Syndrome / Q000382:microbiology / Q000473:pathology* / Q000503:physiopathology*; D013211:Staphylococcus aureus / Q000472:pathogenicity*; D018089:Superantigens
D015820:Cadherins; D051183:Desmoglein 1; D005083:Exfoliatins; D018089:Superantigens; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases