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Hsp multichaperone complex buffers pathologically modified Tau

Author

Listed:
  • Antonia Moll

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Multidisciplinary Sciences)

  • Lisa Marie Ramirez

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Multidisciplinary Sciences)

  • Momchil Ninov

    (Bioanalytical Mass Spectrometry Group
    University Medical Center Goettingen, Institute of Clinical Chemistry, Bioanalytics)

  • Juliane Schwarz

    (Bioanalytical Mass Spectrometry Group
    University Medical Center Goettingen, Institute of Clinical Chemistry, Bioanalytics)

  • Henning Urlaub

    (Bioanalytical Mass Spectrometry Group
    University Medical Center Goettingen, Institute of Clinical Chemistry, Bioanalytics)

  • Markus Zweckstetter

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Multidisciplinary Sciences)

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.

Suggested Citation

  • Antonia Moll & Lisa Marie Ramirez & Momchil Ninov & Juliane Schwarz & Henning Urlaub & Markus Zweckstetter, 2022. "Hsp multichaperone complex buffers pathologically modified Tau," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31396-z
    DOI: 10.1038/s41467-022-31396-z
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    References listed on IDEAS

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