TY - JOUR
T1 - DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation
AU - Hou, Zhiqiang
AU - Wydorski, Pawel M.
AU - Perez, Valerie A.
AU - Mendoza-Oliva, Aydé
AU - Ryder, Bryan D.
AU - Mirbaha, Hilda
AU - Kashmer, Omar
AU - Joachimiak, Lukasz A.
N1 - Funding Information:
This work was supported by grants to L.A.J from the Marie Effie Cain Endowed Scholarship, a Chan Zuckerberg Initiative Collaborative Science Award (2018-191983), and a Bright Focus Foundation grant (A2019060). We appreciate the help of the Molecular Biophysics Resource core, Structural Biology Laboratory, Biomolecular Nuclear Magnetic Resonance Facility, Cryo-Electron Microscopy Facility, and Proteomics Core Facility at the University of Texas Southwestern Medical Center. We thank Dailu Chen for helping in analysis of the XL-MS monolink and looplink data. We also thank members of the Joachimiak lab for reading and providing critical comments on the paper.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25635-y
DO - 10.1038/s41467-021-25635-y
M3 - Article
C2 - 34504072
AN - SCOPUS:85114661405
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5338
ER -