DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation

Zhiqiang Hou, Pawel M. Wydorski, Valerie A. Perez, Aydé Mendoza-Oliva, Bryan D. Ryder, Hilda Mirbaha, Omar Kashmer and Lukasz A. Joachimiak ()
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Zhiqiang Hou: University of Texas Southwestern Medical Center
Pawel M. Wydorski: University of Texas Southwestern Medical Center
Valerie A. Perez: University of Texas Southwestern Medical Center
Aydé Mendoza-Oliva: University of Texas Southwestern Medical Center
Bryan D. Ryder: University of Texas Southwestern Medical Center
Hilda Mirbaha: University of Texas Southwestern Medical Center
Omar Kashmer: University of Texas Southwestern Medical Center
Lukasz A. Joachimiak: University of Texas Southwestern Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Molecular chaperones, including Hsp70/J-domain protein (JDP) families, play central roles in binding substrates to prevent their aggregation. How JDPs select different conformations of substrates remains poorly understood. Here, we report an interaction between the JDP DnaJC7 and tau that efficiently suppresses tau aggregation in vitro and in cells. DnaJC7 binds preferentially to natively folded wild-type tau, but disease-associated mutants in tau reduce chaperone binding affinity. We identify that DnaJC7 uses a single TPR domain to recognize a β-turn structural element in tau that contains the 275VQIINK280 amyloid motif. Wild-type tau, but not mutant, β-turn structural elements can block full-length tau binding to DnaJC7. These data suggest DnaJC7 preferentially binds and stabilizes natively folded conformations of tau to prevent tau conversion into amyloids. Our work identifies a novel mechanism of tau aggregation regulation that can be exploited as both a diagnostic and a therapeutic intervention.

Date: 2021
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DOI: 10.1038/s41467-021-25635-y

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