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Determinants of Staphylococcus aureus PSMα3 Cross-α Fibrils Toxicity

54 Pages Posted: 10 Jul 2019 Sneak Peek Status: Review Complete

See all articles by Einav Tayeb-Fligelman

Einav Tayeb-Fligelman

Technion-Israel Institute of Technology - Department of Biology

Nir Salinas

Technion-Israel Institute of Technology - Department of Biology

Orly Tabachnikov

Technion-Israel Institute of Technology - Department of Biology

Meytal Landau

Technion-Israel Institute of Technology - Department of Biology

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Abstract

Members of the phenol-soluble modulin (PSM) peptide family secreted by Staphylococcus aureus perform various virulence activities, some of which are mediated by the formation of amyloid fibrils of diverse architectures. Specifically, PSMα1 and PSMα4 structure the S. aureus biofilm by assembling into robust cross-β amyloid fibrils composed of tightly mated β-sheets. PSMα3, in contrast, the most cytotoxic member of the family, assembles into cross-α amyloid-like fibrils in which α-helices stack perpendicular to the fibril axis into tightly mated sheets. In this work, we have conducted extensive analyses of the structural and toxic properties of PSMα3 derivatives and mutants, along with crystal structure determination of three single-point alanine mutants showing cross-α structural polymorphism. The findings suggest that interactions with the cell membrane and cytotoxicity are regulated by inter- and intra-helical electrostatic interactions within the cross-α fibril. Using confocal and scanning electron microscopy, we demonstrated co-localization of PSMα3 aggregates and membranes, which was associated with massive cell deformation. Taken together, the process of cross-α fibrillation, along with positive charges, serve as critical determinants of PSMα3 cytotoxicity against human cells. Overall, our results provide mechanistic insight into PSMα3 cytotoxicity, and offer the basis for design of agents to combat staphylococcal virulence.

Keywords: Amyloid, X-ray microcrystallography, PSMalpha3, fiber diffraction, cross-alpha

Suggested Citation

Tayeb-Fligelman, Einav and Salinas, Nir and Tabachnikov, Orly and Landau, Meytal, Determinants of Staphylococcus aureus PSMα3 Cross-α Fibrils Toxicity (July 10, 2019). STRUCTURE-D-19-00196. Available at SSRN: https://ssrn.com/abstract=3417465 or http://dx.doi.org/10.2139/ssrn.3417465
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Einav Tayeb-Fligelman

Technion-Israel Institute of Technology - Department of Biology ( email )

Israel

Nir Salinas

Technion-Israel Institute of Technology - Department of Biology ( email )

Israel

Orly Tabachnikov

Technion-Israel Institute of Technology - Department of Biology

Israel

Meytal Landau (Contact Author)

Technion-Israel Institute of Technology - Department of Biology ( email )

Israel

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