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S. aureus is one of the most important causes of infectious diseases in hospitalized individuals and outpatients. The majority of clinical isolates secretes large amounts of the small membrane pore-forming α-toxin, alias α-hemolysin, which serves as an important virulence factor of this organism. The identification of A Disintegrin And Metalloprotease (ADAM10) as its high affinity receptor held great promise for a better understanding of the processes underlying membrane damage by α-toxin. Twelve years on however, the molecular details of initial toxin binding to target cells remain elusive. Because we noted that several murine cell lines were resilient to α-toxin, we considered the possibility that murine ADAM10 could be less efficient a receptor, as compared to human or bovine orthologues. Accordingly, we sought to identify amino acid residues in ADAM10, which could explain species-dependent functionality as receptor for α-toxin. Our work led to the finding that replacement of a single glutamine residue (Q666) in murine ADAM10 with corresponding glutamic acid (E665) of human or bovine ADAM10 enhances significantly the binding and consequent cytotoxicity of α-toxin. Consistently, a synthetic peptide comprising E665 mitigated α-toxin-dependent hemolysis. In multicellular organisms, E665 is highly conserved, but mice and several other members of the taxon glires evolved glutamine at the corresponding position. The residue is located in a short membrane proximal, extracellular region of ADAM10. Taken together, available structural information, in silico docking, and functional data suggests that α-toxin monomers could bind to cellular membranes via this so-called stalk region of ADAM10 and phosphocholine. |
