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

Author

Listed:
  • Javier Oroz

    (German Center for Neurodegenerative Diseases (DZNE)
    IQFR-CSIC)

  • Bliss J. Chang

    (Max Planck Institute for Biophysical Chemistry)

  • Piotr Wysoczanski

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Biophysical Chemistry)

  • Chung-Tien Lee

    (Max Planck Institute for Biophysical Chemistry)

  • Ángel Pérez-Lara

    (Max Planck Institute for Biophysical Chemistry)

  • Pijush Chakraborty

    (German Center for Neurodegenerative Diseases (DZNE))

  • Romina V. Hofele

    (Max Planck Institute for Biophysical Chemistry)

  • Jeremy D. Baker

    (University of South Florida)

  • Laura J. Blair

    (University of South Florida)

  • Jacek Biernat

    (DZNE, CAESAR Research Center)

  • Henning Urlaub

    (Max Planck Institute for Biophysical Chemistry
    University Medical Center)

  • Eckhard Mandelkow

    (DZNE, CAESAR Research Center)

  • Chad A. Dickey

    (University of South Florida)

  • Markus Zweckstetter

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Biophysical Chemistry)

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.

Suggested Citation

  • Javier Oroz & Bliss J. Chang & Piotr Wysoczanski & Chung-Tien Lee & Ángel Pérez-Lara & Pijush Chakraborty & Romina V. Hofele & Jeremy D. Baker & Laura J. Blair & Jacek Biernat & Henning Urlaub & Eckha, 2018. "Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06880-0
    DOI: 10.1038/s41467-018-06880-0
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    Cited by:

    1. Jaime Carrasco & Rosa Antón & Alejandro Valbuena & David Pantoja-Uceda & Mayur Mukhi & Rubén Hervás & Douglas V. Laurents & María Gasset & Javier Oroz, 2023. "Metamorphism in TDP-43 prion-like domain determines chaperone recognition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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