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Structure of biofilm-forming functional amyloid PSMα1 from Staphylococcus aureus
Kasper Holst Hansen1,2, Chang Hyeock Byeon1, Qian Liu2,3
1Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261.
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). PSMα1 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 PSMα1 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 α-helical PSMα1 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 PSMα1 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.
Insights
Pathogenic Staphylococcus aureus forms biofilms using phenol-soluble modulins (PSMs). Researchers determined the structure of PSMα1 amyloid fibrils, revealing insights into biofilm formation and potential therapeutic targets against chronic infections.
Area of Science:
- Microbiology
- Structural Biology
- Biochemistry
Background:
- Staphylococcus aureus biofilms are resistant to treatment.
- Phenol-soluble modulins (PSMs) form amyloid fibrils essential for biofilm structure.
- PSMα1 initiates biofilm formation by cross-seeding other PSMs into amyloid structures.
Purpose of the Study:
- Determine the high-resolution structure of the major PSMα1 fibril form.
- Elucidate the mechanism of PSM functional amyloid formation and conformational changes.
- Provide a framework for developing therapeutics against S. aureus infections.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to obtain a 3.5 Å resolution density map.
- Structural analysis of the PSMα1 fibril.
Main Results:
- A left-handed cross-β fibril structure composed of two C2-symmetric U-shaped protofilaments was revealed.
- Subunits within the fibril were observed to be unusually tilted out-of-plane.
- Monomeric α-helical PSMα1 exhibited high cytotoxicity, contrasting with the moderate toxicity of the fibril.
Conclusions:
- The study provides mechanistic insights into PSM functional amyloid formation and conformational transformation.
- Understanding PSMα1 assembly and fibril polymorphism offers targets for combating S. aureus biofilms.
- This research establishes a foundation for developing novel therapeutics against antimicrobial resistance.
