Post-translational modifications of Hsp90 and translating the chaperone code

Area of Science:

• Molecular biology
• Cellular stress response
• Protein homeostasis

Background:

• Cells synthesize proteins rapidly, risking aggregation of hydrophobic protein surfaces.
• Molecular chaperones, such as Heat Shock Protein 90 (Hsp90), evolved to prevent protein aggregation and ensure proper folding and assembly.
• Hsp90 is a crucial chaperone for over 300 client proteins involved in vital cellular processes like growth, cell cycle, and signal transduction.

Purpose of the Study:

• To review the regulatory roles of various post-translational modifications (PTMs) on Hsp90 function.
• To discuss how Hsp90's modification state influences cellular responses to Hsp90-targeted therapies.
• To highlight the complexity of the 'chaperone code' in modulating Hsp90 activity.

Main Methods:

• Literature review of existing research on Hsp90 post-translational modifications.
• Analysis of studies investigating the impact of PTMs on Hsp90 chaperone activity.
• Discussion of the link between Hsp90 modification status and therapeutic sensitivity.

Main Results:

• Numerous PTMs, including phosphorylation, acetylation, SUMOylation, methylation, O-GlcNAcylation, and ubiquitination, are reported to regulate Hsp90 function.
• These modifications alter Hsp90's chaperone activity, impacting diverse cellular pathways.
• The modification state of Hsp90 significantly affects cellular sensitivity to drugs targeting its chaperone function.

Conclusions:

• PTMs are critical regulators of Hsp90 chaperone activity, influencing a wide array of cellular processes.
• Understanding the combinatorial 'chaperone code' of Hsp90 PTMs is essential for deciphering its full regulatory network.
• Knowledge of Hsp90 modification states can inform the development and application of targeted cancer therapies.