Hsp multichaperone complex buffers pathologically modified Tau

Antonia Moll, Lisa Marie Ramirez, Momchil Ninov, Juliane Schwarz, Henning Urlaub and Markus Zweckstetter ()
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Antonia Moll: German Center for Neurodegenerative Diseases (DZNE)
Lisa Marie Ramirez: German Center for Neurodegenerative Diseases (DZNE)
Momchil Ninov: Bioanalytical Mass Spectrometry Group
Juliane Schwarz: Bioanalytical Mass Spectrometry Group
Henning Urlaub: Bioanalytical Mass Spectrometry Group
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31396-z

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