Prion propagation by Hsp40 molecular chaperones

Area of Science:

• Molecular biology
• Biochemistry
• Cell biology

Background:

• Yeast prions are proteins that misfold into amyloid-like fibrils, propagating by templating native proteins.
• Molecular chaperones, including Hsp40s and Hsp70s, are crucial for managing prion propagation.
• Hsp40 co-chaperones bind non-native proteins, facilitating their interaction with Hsp70s for refolding or degradation.

Purpose of the Study:

• To investigate the mechanism by which Hsp40 co-chaperones recognize and interact with amyloid-like prion conformers.
• To elucidate the role of substrate selectivity in Hsp40-mediated regulation of prion assembly.
• To understand how distinct Hsp40s can exert opposing effects on prion propagation.

Main Methods:

• Analysis of yeast prion protein domains enriched in glutamine and asparagine residues.
• Investigating the binding interactions between specific Hsp40 co-chaperones (Ydj1, Sis1) and prion protein regions (e.g., Rnq1).
• Assessing the functional consequences of these interactions on prion assembly and propagation in yeast models.

Main Results:

• Hsp40 co-chaperones exhibit selective binding to amyloid-like prion conformers.
• Distinct Hsp40s, such as Type I Ydj1 and Type II Sis1, bind to different regions of the prion protein Rnq1.
• This differential binding leads to opposing effects: Ydj1 inhibits, while Sis1 promotes [RNQ(+)] prion assembly.

Conclusions:

• Substrate selectivity is a key mechanism by which Hsp40 co-chaperones regulate yeast prion propagation.
• Distinct Hsp40s can target specific steps in the prion lifecycle, influencing assembly and stability.
• Understanding these interactions provides insights into chaperone-mediated control of protein aggregation and prion diseases.