Journal Article

DZNE-2020-06630

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex.

Oroz, J. (First author)DZNE* ; Chang, B. J. ; Wysoczanski, P.DZNE* ; Lee, C.-T. ; Pérez-Lara, Á. ; Chakraborty, P.DZNE* ; Hofele, R. V. ; Baker, J. D. ; Blair, L. J. ; Biernat, J.DZNE* ; Urlaub, H. ; Mandelkow, E.DZNE* ; Dickey, C. A. ; Zweckstetter, M. (Last author)DZNE*

2018
Nature Publishing Group UK [London]

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Please use a persistent id in citations: 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.

Keyword(s): Biocatalysis: drug effects (MeSH) ; HSP90 Heat-Shock Proteins: chemistry (MeSH) ; HSP90 Heat-Shock Proteins: metabolism (MeSH) ; HSP90 Heat-Shock Proteins: toxicity (MeSH) ; Humans (MeSH) ; Magnetic Resonance Spectroscopy (MeSH) ; Models, Molecular (MeSH) ; Phosphorylation: drug effects (MeSH) ; Protein Binding: drug effects (MeSH) ; Protein Conformation (MeSH) ; Tacrolimus Binding Proteins: chemistry (MeSH) ; Tacrolimus Binding Proteins: metabolism (MeSH) ; Tacrolimus Binding Proteins: toxicity (MeSH) ; tau Proteins: chemistry (MeSH) ; tau Proteins: metabolism (MeSH) ; tau Proteins: toxicity (MeSH) ; HSP90 Heat-Shock Proteins ; tau Proteins ; Tacrolimus Binding Proteins ; tacrolimus binding protein 5

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Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)
2. Structural Principles of Neurodegeneration (AG Mandelkow 1)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2018

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