Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

Autor: Mok SA; Department of Neurology, University of California at San Francisco, San Francisco, CA, USA., Condello C; Department of Neurology, University of California at San Francisco, San Francisco, CA, USA., Freilich R; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Gillies A; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Arhar T; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Oroz J; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany., Kadavath H; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany., Julien O; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Assimon VA; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Rauch JN; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Dunyak BM; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA., Lee J; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA., Tsai FTF; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA., Wilson MR; llawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, New South Wales, Australia., Zweckstetter M; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.; Max-Planck-Institut für Biophysikalische Chemie, Goettingen, Germany.; Department of Neurology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany., Dickey CA; Department of Molecular Medicine and Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL, USA., Gestwicki JE; Department of Neurology, University of California at San Francisco, San Francisco, CA, USA. jason.gestwicki@ucsf.edu.; Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA. jason.gestwicki@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2018 May; Vol. 25 (5), pp. 384-393. Date of Electronic Publication: 2018 Apr 30.
DOI: 10.1038/s41594-018-0057-1
Abstrakt: A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease.
Databáze: MEDLINE
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