The dynamic triage interplay of Hsp90 with its chaperone cycle and client binding

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Heat shock protein 90 (Hsp90) is a vital molecular chaperone regulating protein homeostasis.
• Its function is intrinsically linked to its conformational plasticity, influenced by ATPase activity and client protein interactions.
• Understanding the dynamic molecular transitions of Hsp90 is essential for comprehending its role in health and disease.

Purpose of the Study:

• To elucidate the dynamic conformational and functional transitions of E. coli Hsp90 (HtpG) throughout its chaperone cycle.
• To provide atomic-level insights into how ATP binding, hydrolysis, and client engagement modulate Hsp90's structure and dynamics.
• To reveal the interplay between conformation, dynamics, nucleotide state, and client interactions in Hsp90's mechanism.

Main Methods:

• Solution Nuclear Magnetic Resonance (NMR) spectroscopy was employed to study Hsp90 dynamics.
• Analysis focused on conformational and dynamic shifts in HtpG in response to ATP binding, hydrolysis, and client engagement.

Main Results:

• ATP binding to HtpG induces slow-exchanging conformations, representing transition states between open and closed forms.
• ATP hydrolysis drives HtpG into a compact conformation.
• Client binding acts as an allosteric switch, enhancing HtpG's chaperone activity through dynamic priming.

Conclusions:

• Hsp90's functional mechanism is characterized by significant conformational fluctuations, particularly in nucleotide-binding and transition regions.
• Atomic-level insights reveal how nucleotide binding/hydrolysis and client interactions dynamically regulate Hsp90's conformation and activity.
• These findings illuminate the intricate molecular basis of Hsp90's chaperone function.