The Mutability of Yeast Prions.

Area of Science:

• Biochemistry
• Molecular Biology
• Prion Biology

Background:

• Prions replicate via self-templating, with errors potentially creating new variants.
• Previous studies suggested limited mutability in yeast [PSI+ ] prion variants.
• The heat shock protein Hsp104's role in restricting prion strain variation was recently highlighted.

Purpose of the Study:

• To investigate whether altering Hsp104 activity influences prion variant mutability.
• To determine if previously identified faithful-propagating variants can mutate under modified chaperone conditions.
• To explore the evolutionary potential of transmutable prion variants.

Main Methods:

• Manipulating Hsp104 activity in yeast by overexpressing wild-type Hsp104 or a hypoactive mutant (Hsp104TM).
• Assessing prion variant propagation and structural changes under altered Hsp104 conditions.
• Comparing variant behavior in modified yeast cells versus wild-type cells.

Main Results:

• Two variants, previously considered faithful-propagating, generated new structures stabilized by hypoactive Hsp104.
• Most transmutable variants identified under Hsp104 overexpression were previously recognized.
• Transmutable variants primarily altered VH, VK, or VL structures, with four variants showing no mutation across conditions.

Conclusions:

• A significant number of [PSI+ ] prion variants are indeed faithful-propagating.
• Even transmutable variants exhibit limited evolution, changing only to specific structural types.
• Hsp104 activity critically influences the detection and potential evolution of prion variants.