Exfoliative toxins of Staphylococcus aureus

Abstract

Staphylococcus aureus is an important pathogen of humans and livestock. It causes a diverse array of diseases, ranging from relatively harmless localized skin infections to life-threatening systemic conditions. Among multiple virulence factors, staphylococci secrete several exotoxins directly associated with particular disease symptoms. These include toxic shock syndrome toxin 1 (TSST-1), enterotoxins, and exfoliative toxins (ETs). The latter are particularly interesting as the sole agents responsible for staphylococcal scalded skin syndrome (SSSS), a disease predominantly affecting infants and characterized by the loss of superficial skin layers, dehydration, and secondary infections. The molecular basis of the clinical symptoms of SSSS is well understood. ETs are serine proteases with high substrate specificity, which selectively recognize and hydrolyze desmosomal proteins in the skin. The fascinating road leading to the discovery of ETs as the agents responsible for SSSS and the characterization of the molecular mechanism of their action, including recent advances in the field, are reviewed in this article.

Keywords: Staphylococcus aureus; bullous impetigo; epidermolytic toxin; exfoliative toxin; staphylococcal scalded skin syndrome.

Figure 1

Exfoliative toxins belong to the chymotrypsin family of serine proteases and are structurally similar to staphylococcal glutamylendopeptidase (V8 protease). (A) Ribbon representation of the crystal structure of glutamylendopeptidase (left) and ETA (right). The catalytic triad residues Asp, His, and Ser are depicted in a stick model in red, blue, and yellow, respectively. Except for an additional helix characteristic of the exfoliative toxins and the conformation of some surface loops, the overall fold of both enzymes is almost identical. (B) The superimposition of the catalytic triad residues of glutamylendopeptidase and the corresponding residues of ETA, shown in red and light blue, respectively, demonstrates that this important part of the catalytic machinery is well developed in the toxin structure. Conversely, the oxyanion hole is not preformed in the structure of ETA, as demonstrated by the different orientations of the carbonyl oxygen of the Pro192-Gly193 peptide bond in ETA and the corresponding Gly166-Gly167 peptide bond in glutamylendopeptidase (dashed circle). The amino acid numbering is according to the Protein Data Bank (PDB) entries 1EXF (ETA) and 2O8L (glutamylendopeptidase; numbers in parentheses).

Figure 2

Exclusive specificity of exfoliative toxin A for human desmoglein 1 is dictated by primary interactions at the P1 specificity pocket and by secondary interactions with tertiary structural elements located away from the site of cleavage. (A) Homology model of domains EC3 and EC4 of human desmoglein 1 based on the crystal structure of domains EC3 and EC4 of Xenopus laevis C-cadherin (PDB ID: 1L3W). The glutamic acid residue determining the primary interaction at the P1 site of the enzyme and adjacent to the cleavage site is shown by the arrow (red). Distant sites of secondary interactions are marked in blue (according to [68]). Calcium ions, which stabilize the desmoglein structure and are essential for cleavage, are shown as grey spheres. (B) Sequence comparison of the EC3 domain of desmoglein 1 from different species explains the exclusive specificity of ETA for human and mouse desmoglein 1. Conserved amino acid sequences in the EC3 domains of the analysed species differ primarily in the region recognized by ETA. Colour coding as in panel A. (UniProt accession numbers for the desmoglein sequences: Q02413 human, Q7TSF1 mouse, Q9GKQ8 dog, Q3BDI7 pig).

Figure 3

Differential distribution of desmoglein isoforms in the epidermis [80] explains the exfoliative-toxin-induced splitting at the stratum granulosum. Schematic representation of the desmoglein distribution in (A) healthy skin and (B) skin exposed to exfoliative toxin. In all strata, except the stratum granulosum, the exfoliative-toxin-mediated hydrolysis of desmoglein 1 (Dsg-1) is compensated by desmoglein 3 (Dsg-3). Dsg-3 is absent in the stratum granulosum, which explains the cell detachment and the splitting of the epidermal layers upon the hydrolysis of Dsg-1.