Use of a Stereochemical Strategy To Probe the Mechanism of Phenol-Soluble Modulin ?3 Toxicity.

ABSTRACT: Phenol-soluble modulin ?3 (PSM?3) is a cytotoxic peptide secreted by virulent strains of Staphylococcus aureus. We used a stereochemical strategy to examine the mechanism of PSM?3-mediated toxicity. One hypothesis is that PSM?3 toxicity requires fibril formation; an alternative is that toxicity is caused by soluble forms of PSM?3, possibly oligomeric. We find that the unnatural enantiomer (D residues) displays cytotoxicity comparable to that of L-PSM?3. Racemic PSM?3 is similarly toxic to enantiopure PSM?3 (L or D) under some conditions, but the toxicity is lost under conditions that cause racemic PSM?3 to aggregate. A crystal structure of racemic PSM?3-NH2 displays an ?-helical secondary structure and a packing pattern that is reminiscent of the cross-? arrangement recently discovered in crystals of L-PSM?3. Our data suggest that the cytotoxicity of PSM?3 does not depend on stereospecific engagement of a target protein or other chiral macromolecule, an observation that supports a mechanism based on membrane disruption. In addition, our data support the hypothesis that toxicity is exerted by a soluble form rather than an insoluble fibrillar form.

SUBMITTER: Yao Z 

PROVIDER: S-EPMC6520131 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature