Abstract

Molecular chaperones such as the Hsp90 chaperone are the first line of the cellular defense system against protein damage and aggregation. The chaperones are part of the proteostasis network, the natural defense system against protein damage problems. Hsp90 interacts in vivo and in vitro with the Tau protein, the molecular basis of this interaction remained enigmatic. We disclosed a structural model of the Hsp90-Tau complex, showing the Tau protein behaves as a bona fide client of the Hsp90 chaperone. Hsp90 binds to a broad region in Tau that includes the aggregation-prone repeats. Our model resolves the paradox on how Hsp90 specifically selects for late folding intermediates but also intrinsically disordered proteins such as Tau. Our data offer a mechanistic understanding how molecular chaperones can deal with aggregates in neurodegenerative diseases.