Extreme amyloid polymorphism in Staphylococcus aureus virulent PSMα peptides

Members of the Staphylococcus aureus phenol-soluble modulin (PSM) peptide family are secreted as functional amyloids that serve diverse roles in pathogenicity and may be present as full-length peptides or as naturally occurring truncations. We recently showed that the activity of PSM alpha 3, the most toxic member, stems from the formation of cross-alpha fibrils, which are at variance with the cross-beta fibrils linked with eukaryotic amyloid pathologies. Here, we show that PSM alpha 1 and PSM alpha 4, involved in biofilm structuring, form canonical cross-beta amyloid fibrils wherein beta-sheets tightly mate through steric zipper interfaces, conferring high stability. Contrastingly, a truncated PSM alpha 3 has antibacterial activity, forms reversible fibrils, and reveals two polymorphic and atypical beta-rich fibril architectures. These architectures are radically different from both the cross-alpha fibrils formed by full-length PSM alpha 3, and from the canonical cross-beta fibrils. Our results point to structural plasticity being at the basis of the functional diversity exhibited by S. aureus PSM alpha s.