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Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity.

Accepted version
Peer-reviewed

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Authors

De, Suman 
Horrocks, Mathew H 
Kjaergaard, Magnus 

Abstract

As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.

Description

Keywords

Amyloid, Fluorescence, HSP70 Heat-Shock Proteins, Humans, Protein Aggregation, Pathological, Single Molecule Imaging, tau Proteins

Journal Title

ACS Chem Biol

Conference Name

Journal ISSN

1554-8929
1554-8937

Volume Title

13

Publisher

American Chemical Society (ACS)
Sponsorship
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
European Research Council (669237)
D.K. acknowledges funding from the ERC (grant #669237). M.K. acknowledges fellowships from the Danish research council and the Lundbeck Foundation. F.K. acknowledges funding from the Augustus Newman foundation and the ERC. M.H.H. acknowledges funding from the Herchel Smith Fund and Christ’s College Cambridge. S.D. was funded by a Marie Skłodowska-Curie Individual Fellowship. P.F. acknowledges funding from the Boehringer Ingelheim Fonds and the Studienstiftung des deutschen Volkes. We acknowledge S. Qamar for providing the tau protein used for this study.