Structural mechanisms of chaperone mediated protein disaggregation

Area of Science:

• Molecular biology
• Biochemistry
• Cell biology

Background:

• ClpB/Hsp104 and Hsp70 are molecular chaperones that utilize ATP hydrolysis.
• These chaperones are crucial for disaggregating protein aggregates and complexes, and for protein translocation across membranes.

Purpose of the Study:

• To elucidate the distinct mechanisms of protein aggregate dissociation employed by ClpB/Hsp104 and Hsp70 chaperones.
• To understand the regulatory mechanisms governing the activity of disaggregating chaperones.

Main Methods:

• Analysis of AAA+ protein family structure and function, focusing on ClpB/Hsp104 hexamers.
• Investigation of proposed force-generation mechanisms for Hsp70, including power-stroke, passive capture, and entropic pulling.
• Examination of chaperone regulation by co-chaperones and substrate recruitment.

Main Results:

• ClpB/Hsp104, an AAA+ protein, disaggregates stable protein structures via ATP-driven conformational changes and pore engagement.
• Hsp70 force generation mechanisms are diverse and less understood, with proposed models including active power-stroke, passive capture, and entropic pulling.
• Disaggregase activity is essential for thermotolerance but requires strict regulation by co-chaperones to prevent uncontrolled dissociation.

Conclusions:

• ClpB/Hsp104 employs a power-stroke mechanism for aggregate dissociation, while Hsp70 mechanisms are varied.
• Co-chaperone-mediated regulation ensures precise activation of disaggregating chaperones, balancing their beneficial and potentially harmful functions.
• Understanding these chaperone systems is key to cellular proteostasis and stress response.