Hsp90-Tau complex reveals molecular basis for specificity in chaperone action

Area of Science:

• Molecular biology
• Structural biology
• Biochemistry

Background:

• Cellular protein folding is regulated by molecular chaperone systems, primarily Hsp70 and Hsp90.
• Hsp70 functions early, while Hsp90 acts later in the protein folding pathway.
• The substrate specificity and precise timing mechanism of Hsp90 remain poorly understood.

Purpose of the Study:

• To elucidate the molecular basis of Hsp90 substrate specificity.
• To understand how Hsp90 distinguishes late folding intermediates from early ones.
• To model the interaction between Hsp90 and its disease-associated substrate, the Tau protein.

Main Methods:

• Generation of a structural model of the Hsp90-Tau complex.
• Analysis of the Hsp90 substrate-binding interface.
• Investigation of Hsp90's recognition mechanism for hydrophobic residues.

Main Results:

• Hsp90 binds broadly across the Tau protein, including aggregation-prone regions.
• A large Hsp90 binding interface (106 Å) facilitates numerous low-affinity contacts.
• Hsp90 recognizes scattered hydrophobic residues in late folding intermediates, distinct from Hsp70 binding sites.

Conclusions:

• Hsp90's broad, low-affinity binding mechanism explains its specificity for late folding intermediates.
• This mechanism also accounts for Hsp90's ability to bind intrinsically disordered proteins.
• The structural model provides insight into the functional coordination between Hsp70 and Hsp90 chaperone systems.