DnaJC7 binds natively folded structural elements in tau to inhibit amyloid formation
Zhiqiang Hou1,2, Pawel M Wydorski1,3, Valerie A Perez1,3
1Center for Alzheimer's and Neurodegenerative Diseases, University of Texas Southwestern Medical Center, Dallas, TX, United States.
Nature Communications
|September 10, 2021
Summary
J-domain proteins (JDPs) like DnaJC7 bind natively folded tau, preventing toxic aggregation. This chaperone interaction offers new diagnostic and therapeutic strategies for tauopathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Molecular chaperones, such as Hsp70/J-domain protein (JDP) families, are crucial for preventing protein aggregation.
- The precise mechanisms by which JDPs select specific substrate conformations are not well understood.
Purpose of the Study:
- To investigate the interaction between the JDP DnaJC7 and tau protein.
- To elucidate how DnaJC7 binding suppresses tau aggregation.
- To identify the structural basis for DnaJC7's substrate specificity.
Main Methods:
- In vitro aggregation assays.
- Cell-based experiments.
- Structural analysis of chaperone-substrate interactions.
Main Results:
- DnaJC7 efficiently suppresses tau aggregation both in vitro and in cellular models.
- DnaJC7 preferentially binds to natively folded wild-type tau, with reduced affinity for disease-associated tau mutants.
- DnaJC7 recognizes a specific β-turn structural element (275VQIINK280) within tau via its TPR domain.
Conclusions:
- DnaJC7 stabilizes natively folded tau conformations, thereby preventing its conversion into amyloid aggregates.
- This interaction represents a novel mechanism for regulating tau aggregation.
- The DnaJC7-tau interaction holds potential for developing diagnostic and therapeutic interventions for tauopathies.
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