Reciprocal Interactions between Membrane Bilayers and S. aureus PSMα3 Cross-α Amyloid Fibrils Account for Species-Specific Cytotoxicity |
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Authors: | Ravit Malishev Einav Tayeb-Fligelman Shimrit David Michael M Meijler Meytal Landau Raz Jelinek |
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Institution: | 1. Department of Chemistry, Ben Gurion University of the Negev, Beer Sheva 84105, Israel;2. Ilse Katz Institute for Nanotechnology, Ben Gurion University of the Negev, Beer Sheva 84105, Israel;3. Department of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel |
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Abstract: | Phenol-soluble modulin α3 (PSMα3) is a functional amyloid secreted by the pathogenic bacterium Staphylococcus aureus. This 22-residue peptide serves as a key virulence determinant, toxic to human cells via the formation of unique cross-α amyloid-like fibrils. We demonstrate that bilayer vesicles accelerated PSMα3 fibril formation, and the fibrils, in turn, inserted deeply into bilayers mimicking mammalian cell membranes, accounting for PSMα3 cellular toxicity. Importantly, a mere amphipathic helical conformation was not a sufficient determinant for membrane-activity of PSMα3, pointing to the functional role of cross-α fibrils. In contrast to deep insertion of PSMα3 into mammalian membrane bilayers, the peptide only interacted with the surface of bilayers mimicking bacterial membranes, which might be related to its lack of antibacterial activity. Together, our data provide mechanistic insight into species-specific toxicity of a key bacterial amyloid virulence factor via reciprocal interactions with membranes, and open new perspectives into amyloid-related cytotoxicity mediated by helical fibril structures. |
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Keywords: | PSMα3 phenol-soluble modulin α3 AFM atomic force microscopy CD circular dichroism FRET Förster resonance energy transfer phenol-soluble modulins cross-alpha fibril amyloid peptides amyloid–membrane interaction |
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