One domain fits all: Using disordered regions to sequester misfolded proteins

Area of Science:

• Cell Biology
• Protein Homeostasis
• Molecular Chaperones

Background:

• Small heat shock proteins (sHsps) are ATP-independent molecular chaperones.
• sHsps play a crucial role in cellular proteostasis by preventing protein misfolding and aggregation.

Purpose of the Study:

• To investigate the mechanism by which the yeast sHsp Hsp42 interacts with and sequesters misfolded proteins.
• To elucidate the role of intrinsically disordered regions in sHsp function.

Main Methods:

• Yeast genetics and biochemistry
• Protein-misfolding assays
• Microscopy techniques to visualize protein localization.

Main Results:

• The yeast sHsp Hsp42 utilizes a prion-like intrinsically disordered domain for substrate binding.
• Hsp42 effectively binds and sequesters misfolded proteins within distinct cellular compartments known as protein deposition sites.
• This sequestration mechanism contributes to cellular defense against proteotoxicity.

Conclusions:

• The intrinsically disordered domain of Hsp42 is essential for its chaperone activity and sequestration function.
• Hsp42-mediated sequestration of misfolded proteins is a key strategy for maintaining cellular proteostasis under stress conditions.
• This study provides novel insights into the functional role of prion-like domains in chaperone proteins.