Establishing Order Through Disorder by the Hsp90 Molecular Chaperone.

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Heat Shock Protein 90 (Hsp90) is a crucial molecular chaperone essential for protein homeostasis (proteostasis) in eukaryotes.
• Hsp90 is highly abundant and operates in the cytoplasm and nucleus, regulating numerous client proteins and complexes.
• The Hsp90 interactome is extensive, involving approximately 25% of the proteome in budding yeast.

Purpose of the Study:

• To review recent advancements in understanding the molecular mechanisms of Hsp90-client interactions.
• To elucidate how Hsp90 recognizes and associates with a diverse range of target proteins.
• To develop a model explaining Hsp90's role in maintaining proteostasis.

Main Methods:

• Review of existing literature on Hsp90-client interactions.
• Analysis of available Hsp90-client structural data.
• Assessment of recently identified Hsp90-client peptide complexes.

Main Results:

• Hsp90 recognizes client proteins through specific sites, often within intrinsically disordered regions (IDRs).
• Two primary modes of Hsp90 association: transient regulation via direct IDR recognition, or stable association with unstructured regions formed by chaperone/cochaperone action.
• Intrinsically disordered regions serve as a common recognition property for Hsp90 across diverse clients.

Conclusions:

• Hsp90 utilizes intrinsically disordered regions as a common feature for recognizing a wide array of client proteins.
• This recognition mechanism underpins Hsp90's central role in supporting chaperone action and maintaining cellular proteostasis.
• Understanding Hsp90-client interactions is critical for comprehending the broader proteostatic network.