Differential fibril morphologies and thermostability determine functional roles of Staphylococcus aureus PSM1 and PSM3

Phenol-soluble modulins (PSMs) are virulent peptides secreted by staphylococci that undergo self-assembly into amyloid fibrils. This study focuses on Staphylococcus aureus PSM alpha 1 and PSM alpha 3, which share homologous sequences but exhibit distinct amyloid fibril structures. Upon subjecting PSM alpha 3 to an 80 degrees C heat shock, it fibrillates into cross-beta structures, resulting in the loss of cytotoxic activity. Conversely, PSM alpha 3 cross-alpha fibrils undergo reversible disaggregation upon heat shock, leading to the recovery of cytotoxicity. The differential thermostability probably arises from the presence of hydrogen bonds along the beta-strands within the beta-sheets of the cross-beta fibrils. We propose that the breakdown of PSM alpha 3 fibrils into soluble species, potentially co-aggregating with membrane lipids, is crucial for its toxic process and enables the reversible modulation of its biological activity under stress conditions. In contrast, the formation of robust and irreversible cross-beta fibrils by PSM alpha 1 corresponds to its role in biofilm stability. These findings emphasize how the unique fibril morphologies and thermostability of PSM alpha 1 and PSM alpha 3 shape their functional roles in various environments of S. aureus.