Structural basis for the dynamic chaperoning of disordered clients by Hsp90

Area of Science:

• Molecular biology
• Structural biology
• Biochemistry

Background:

• Heat shock protein 90 (Hsp90) is a crucial molecular chaperone regulating diverse client proteins in cellular processes and disease.
• Understanding Hsp90's client interactions at an atomic level is essential for elucidating its functional cycle.
• The initial open conformation complex of Hsp90 with clients has remained structurally uncharacterized.

Purpose of the Study:

• To determine the solution structure of Hsp90 in its open state when bound to a disordered client.
• To elucidate the mechanism by which Hsp90 engages and interacts with its client proteins.

Main Methods:

• Nuclear magnetic resonance (NMR) spectroscopy was employed to determine the solution structure.
• Studies involved Hsp90 in its open conformation bound to a disordered client protein.

Main Results:

• Hsp90 utilizes two distinct, synergistic binding sites to capture hydrophobic segments of client proteins.
• This bipartite interaction forms a versatile complex that promotes rapid conformational sampling.
• A conserved mechanism for client accommodation across different Hsp90 orthologs and clients was identified.

Conclusions:

• The study reveals a fundamental, bipartite interaction mechanism for Hsp90 client binding in its open state.
• This finding establishes a unified framework for understanding Hsp90's role in regulating client proteins.
• The identified mechanism highlights Hsp90's adaptability in interacting with a wide range of client proteins.