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

Javier Oroz, Bliss J. Chang, Piotr Wysoczanski, Chung-Tien Lee, Ángel Pérez-Lara, Pijush Chakraborty, Romina V. Hofele, Jeremy D. Baker, Laura J. Blair, Jacek Biernat, Henning Urlaub, Eckhard Mandelkow, Chad A. Dickey and Markus Zweckstetter ()
Additional contact information
Javier Oroz: German Center for Neurodegenerative Diseases (DZNE)
Bliss J. Chang: Max Planck Institute for Biophysical Chemistry
Piotr Wysoczanski: German Center for Neurodegenerative Diseases (DZNE)
Chung-Tien Lee: Max Planck Institute for Biophysical Chemistry
Ángel Pérez-Lara: Max Planck Institute for Biophysical Chemistry
Pijush Chakraborty: German Center for Neurodegenerative Diseases (DZNE)
Romina V. Hofele: Max Planck Institute for Biophysical Chemistry
Jeremy D. Baker: University of South Florida
Laura J. Blair: University of South Florida
Jacek Biernat: DZNE, CAESAR Research Center
Henning Urlaub: Max Planck Institute for Biophysical Chemistry
Eckhard Mandelkow: DZNE, CAESAR Research Center
Chad A. Dickey: University of South Florida
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06880-0

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