Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex

Javier Oroz,Eckhard Mandelkow,Chad A Dickey,Laura J Blair,Jeremy D Baker,Bliss J Chang,Chung-Tien Lee,Pijush Chakraborty,Jacek Biernat,Henning Urlaub,Ángel Pérez-Lara,Markus Zweckstetter,Romina V Hofele,Piotr Wysoczanski

doi:10.1038/s41467-018-06880-0

Abstract

The molecular chaperone Hsp90 is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp90, the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. Here, we report the solution structures of human full-length Hsp90 in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer’s disease-related protein Tau. We reveal that the FKBP51/Hsp90 complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp90 dimer resulting in decreased Hsp90 ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau’s proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. Our study defines a conceptual model for dynamic Hsp90/co-chaperone/client recognition.

Highlights

The molecular chaperone Hsp[90] is critical for the maintenance of cellular homeostasis and represents a promising drug target
In the presence of the peptidyl-prolyl isomerase (PPIase) FKBP51, which binds with high affinity and equimolar stoichiometry to the Hsp[90] dimer[28], the overall dimensions further increased (Fig. 1b)
The heat-shock protein 90 (Hsp90)/FKBP51 complex remained open in the presence of nucleotides (Supplementary Figure 1b), despite the ability of nucleotides to promote compact Hsp[90] conformations[25]

Summary

Introduction

The molecular chaperone Hsp[90] is critical for the maintenance of cellular homeostasis and represents a promising drug target. Despite increasing knowledge on the structure of Hsp[90], the molecular basis of substrate recognition and pro-folding by Hsp90/co-chaperone complexes remains unknown. We report the solution structures of human full-length Hsp[90] in complex with the PPIase FKBP51, as well as the 280 kDa Hsp90/FKBP51 complex bound to the Alzheimer’s disease-related protein Tau. We reveal that the FKBP51/Hsp[90] complex, which synergizes to promote toxic Tau oligomers in vivo, is highly dynamic and stabilizes the extended conformation of the Hsp[90] dimer resulting in decreased Hsp[90] ATPase activity. Within the ternary Hsp90/FKBP51/Tau complex, Hsp[90] serves as a scaffold that traps the PPIase and nucleates multiple conformations of Tau’s proline-rich region next to the PPIase catalytic pocket in a phosphorylation-dependent manner. A key finding of our study is that the interaction of the PPIase with Hsp[90] is dynamic and involves Hsp[90] surfaces distinct from other cochaperones, enabling asymmetric chaperone/co-chaperone/ client complexes

Methods

Results

Conclusion