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

Oroz, J., Chang, B. J., Wysoczanski, P., Lee, C. T., Perez-Lara, A., Chakraborty, P., et al. (2018). Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nature Communications, 9: 4532. doi:10.1038/s41467-018-06880-0.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-6E0A-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-AEEF-D
Genre: Journal Article

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 Creators:
Oroz, J., Author
Chang, B. J.1, Author              
Wysoczanski, P.1, Author              
Lee, C. T.2, Author              
Perez-Lara, A.3, Author              
Chakraborty, P., Author
Hofele, R. V.2, Author              
Baker, J. D., Author
Blair, L. J., Author
Biernat, J., Author
Urlaub, H.2, Author              
Mandelkow, E., Author
Dickey, C. A., Author
Zweckstetter, M.1, Author              
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society, ou_578571              
2Research Group of Bioanalytical Mass Spectrometry, MPI for biophysical chemistry, Max Planck Society, ou_578613              
3Department of Neurobiology, MPI for Biophysical Chemistry, Max Planck Society, ou_578595              

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 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.

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Language(s): eng - English
 Dates: 2018-10-31
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41467-018-06880-0
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Title: Nature Communications
Source Genre: Journal
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Pages: 13 Volume / Issue: 9 Sequence Number: 4532 Start / End Page: - Identifier: -