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Use of a Stereochemical Strategy To Probe the Mechanism of Phenol-Soluble Modulin α3 Toxicity

  • Zhihui Yao
    Zhihui Yao
    Graduate Program in Biophysics, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
    More by Zhihui Yao
  • Brian P. Cary
    Brian P. Cary
    Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
  • Craig A. Bingman
    Craig A. Bingman
    Department of Biochemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
  • Chenxuan Wang
    Chenxuan Wang
    Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
  • Dale F. Kreitler
    Dale F. Kreitler
    Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
  • Kenneth A. Satyshur
    Kenneth A. Satyshur
    Department of Bacteriology, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
  • Katrina T. Forest*
    Katrina T. Forest
    Graduate Program in Biophysics,  Department of Chemistry  and  Department of Bacteriology, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
    *[email protected]
  • , and 
  • Samuel H. Gellman*
    Samuel H. Gellman
    Graduate Program in Biophysics  and  Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin 53706, United States
    *[email protected]
Cite this: J. Am. Chem. Soc. 2019, 141, 19, 7660–7664
Publication Date (Web):May 2, 2019
https://doi.org/10.1021/jacs.9b00349
Copyright © 2019 American Chemical Society

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    Abstract

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    Phenol-soluble modulin α3 (PSMα3) is a cytotoxic peptide secreted by virulent strains of Staphylococcus aureus. We used a stereochemical strategy to examine the mechanism of PSMα3-mediated toxicity. One hypothesis is that PSMα3 toxicity requires fibril formation; an alternative is that toxicity is caused by soluble forms of PSMα3, possibly oligomeric. We find that the unnatural enantiomer (D residues) displays cytotoxicity comparable to that of L-PSMα3. Racemic PSMα3 is similarly toxic to enantiopure PSMα3 (L or D) under some conditions, but the toxicity is lost under conditions that cause racemic PSMα3 to aggregate. A crystal structure of racemic PSMα3-NH2 displays an α-helical secondary structure and a packing pattern that is reminiscent of the cross-α arrangement recently discovered in crystals of L-PSMα3. Our data suggest that the cytotoxicity of PSMα3 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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b00349.

    • Model coordinates and structure factors have been deposited in the Protein Data Bank as entry 6NIV; experimental details including peptide synthesis and characterization, X-ray crystallography, cell toxicity assay, FPR2 activation assay, Thioflavin T assay, transmission electron microscopy; X-ray diffraction data collection, fibril diffraction data and analysis, structure solution and refinement; additional comparison of homochiral packing along crystal growth axis; additional cell assay results; additional transition electron microscope results (PDF)

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