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  Hsp multichaperone complex buffers pathologically modified Tau

Moll, A., Ramirez, L. M., Ninov, M., Schwarz, J., Urlaub, H., & Zweckstetter, M. (2022). Hsp multichaperone complex buffers pathologically modified Tau. Nature Communications, 13: 3668. doi:10.1038/s41467-022-31396-z.

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 Creators:
Moll, A.1, Author           
Ramirez, L. M.1, Author           
Ninov, M.2, Author           
Schwarz, J.2, Author           
Urlaub, H.2, Author           
Zweckstetter, Markus1, Author           
Affiliations:
1Department of NMR Based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350124              
2Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350290              

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 Abstract: Alzheimer’s disease is a neurodegenerative disorder in which misfolding and aggregation of pathologically modified Tau is critical for neuronal dysfunction and degeneration. The two central chaperones Hsp70 and Hsp90 coordinate protein homeostasis, but the nature of the interaction of Tau with the Hsp70/Hsp90 machinery has remained enigmatic. Here we show that Tau is a high-affinity substrate of the human Hsp70/Hsp90 machinery. Complex formation involves extensive intermolecular contacts, blocks Tau aggregation and depends on Tau’s aggregation-prone repeat region. The Hsp90 co-chaperone p23 directly binds Tau and stabilizes the multichaperone/substrate complex, whereas the E3 ubiquitin-protein ligase CHIP efficiently disassembles the machinery targeting Tau to proteasomal degradation. Because phosphorylated Tau binds the Hsp70/Hsp90 machinery but is not recognized by Hsp90 alone, the data establish the Hsp70/Hsp90 multichaperone complex as a critical regulator of Tau in neurodegenerative diseases.

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Language(s): eng - English
 Dates: 2022-06-272022
 Publication Status: Published in print
 Pages: 13
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 Rev. Type: -
 Identifiers: DOI: 10.1038/s41467-022-31396-z
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Project name : H.U. is supported by the Deutsche Forschungsgemeinschaft, DFG (SFB1286/2, Project A10 and SFB860/3, Project A10). M.Z. was supported by the European Research Council (ERC) under the EU Horizon 2020 research and innovation program (grant agreement No. 787679)
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Grant ID : 787679
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Nature Communications
Source Genre: Journal
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Pages: 13 Volume / Issue: 13 Sequence Number: 3668 Start / End Page: - Identifier: ISSN: 2041-1723