Abstract
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.
| Translated title of the contribution | Struktur af Biofilm formende funktionel amyloid PSMα1 fra Staphylococcus aureus |
|---|---|
| Original language | English |
| Article number | e2406775121 |
| Journal | Proceedings of the National Academy of Sciences (PNAS) |
| Volume | 121 |
| Issue | 33 |
| Number of pages | 10 |
| ISSN | 0027-8424 |
| DOIs | |
| Publication status | Published - Aug 2024 |
Keywords
- bacterial biofilm
- cryo-EM
- functional amyloid fibril
- phenol soluble modulin PSMa1
- S. aureus