The cytotoxic Staphylococcus aureus PSMα3 reveals a cross-α amyloid-like fibril

Area of Science:

• Microbiology
• Structural Biology
• Biochemistry

Background:

• Amyloids are ordered protein aggregates with roles in disease and physiology across all life forms.
• Functional amyloids in microbes are critical virulence factors, but their structures are often unknown.
• Phenol-soluble modulin α3 (PSMα3) from Staphylococcus aureus is a highly toxic peptide involved in virulence.

Purpose of the Study:

• To determine the fibril structure and function of the Staphylococcus aureus PSMα3 peptide.
• To elucidate the structural basis for the activity of microbial functional amyloids.

Main Methods:

• Crystal structure determination of full-length PSMα3 peptide.
• De novo structure solution at 1.45 angstrom resolution.
• Morphological and tinctorial characterization of PSMα3 fibrils.

Main Results:

• PSMα3 forms elongated fibrils with characteristics of canonical cross-β amyloids.
• The crystal structure revealed a novel "cross-α" amyloid-like architecture.
• Amphipathic α helices stack perpendicular to the fibril axis, forming self-associating sheets.
• This cross-α fibrillation mechanism directly contributes to PSMα3's cytotoxicity.

Conclusions:

• Staphylococcus aureus utilizes a unique cross-α amyloid assembly for its toxic peptide PSMα3.
• This distinct fibril structure is crucial for PSMα3's role in virulence.
• The findings challenge traditional views of amyloid structures and their functions.