Structure of biofilm-forming functional amyloid PSMα1 from Staphylococcus aureus

Biofilm-protected pathogenic Staphylococcus aureus causes chronic infections that are difficult to treat. An essential building block of these biofilms are functional amyloid fibrils that assemble from phenol-soluble modulins (PSMs). PSMa1 cross-seeds other PSMs into cross-β amyloid folds and is therefore a key element in initiating biofilm formation. However, the paucity of high-resolution structures hinders efforts to prevent amyloid assembly and biofilm formation. Here, we present a 3.5 Å resolution density map of the major PSMa1 fibril form revealing a left-handed cross-β fibril composed of two C2-symmetric U-shaped protofilaments whose subunits are unusually tilted out-of-plane. Monomeric a-helical PSMa1 is extremely cytotoxic to cells, despite the moderate toxicity of the cross-β fibril. We suggest mechanistic insights into the PSM functional amyloid formation and conformation transformation on the path from monomer-to- fibril formation. Details of PSMa1 assembly and fibril polymorphism suggest how S. aureus utilizes functional amyloids to form biofilms and establish a framework for developing therapeutics against infection and antimicrobial resistance.