TY  - JOUR
AU  - Oroz, Javier
AU  - Chang, Bliss J
AU  - Wysoczanski, Piotr
AU  - Lee, Chung-Tien
AU  - Pérez-Lara, Ángel
AU  - Chakraborty, Pijush
AU  - Hofele, Romina V
AU  - Baker, Jeremy D
AU  - Blair, Laura J
AU  - Biernat, Jacek
AU  - Urlaub, Henning
AU  - Mandelkow, Eckhard
AU  - Dickey, Chad A
AU  - Zweckstetter, Markus
TI  - Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.
JO  - Nature Communications
VL  - 9
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2020-06630
SP  - 4532
PY  - 2018
AB  - 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.
KW  - Biocatalysis: drug effects
KW  - HSP90 Heat-Shock Proteins: chemistry
KW  - HSP90 Heat-Shock Proteins: metabolism
KW  - HSP90 Heat-Shock Proteins: toxicity
KW  - Humans
KW  - Magnetic Resonance Spectroscopy
KW  - Models, Molecular
KW  - Phosphorylation: drug effects
KW  - Protein Binding: drug effects
KW  - Protein Conformation
KW  - Tacrolimus Binding Proteins: chemistry
KW  - Tacrolimus Binding Proteins: metabolism
KW  - Tacrolimus Binding Proteins: toxicity
KW  - tau Proteins: chemistry
KW  - tau Proteins: metabolism
KW  - tau Proteins: toxicity
KW  - HSP90 Heat-Shock Proteins (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Tacrolimus Binding Proteins (NLM Chemicals)
KW  - tacrolimus binding protein 5 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:30382094
C2  - pmc:PMC6208366
DO  - DOI:10.1038/s41467-018-06880-0
UR  - https://pub.dzne.de/record/140308
ER  -