How Sup35 monomer conformation and amyloid fibril polymorphism determine yeast strain phenotypes

Area of Science:

• Biochemistry
• Structural Biology
• Yeast Genetics

Background:

• The yeast prion protein Sup35 forms amyloid fibrils, leading to distinct prion strains with varying phenotypes.
• Understanding the structural basis of these prion strains and their propagation is crucial for deciphering prion biology.

Purpose of the Study:

• To elucidate the structural mechanisms underlying yeast prion strain diversity using Sup35 variants.
• To correlate fibril structure with prion stability, chaperone accessibility, and propagation efficiency.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine fibril structures.
• Single-monomer force spectroscopy with optical tweezers to probe fibril stability and dynamics.
• Analysis of wild-type and S17R mutant Sup35 variants.

Main Results:

• Four Sup35 variants formed distinct fibril structures with varying stability and chaperone accessibility.
• Fibril structures originated from different monomer conformational ensembles.
• Prion strain strength correlated with low fibril stability and chaperone-binding region accessibility.

Conclusions:

• A structure-based mechanism for yeast prion strain diversity was revealed.
• Findings provide insights into amyloid propagation relevant to human neurodegenerative diseases.