Cawood, EE, Clore, GM and Karamanos, T orcid.org/0000-0003-2297-540X (2022) Microsecond Backbone Motions Modulate the Oligomerization of the DNAJB6 Chaperone. Angewandte Chemie International Edition, 61 (20). e202116403. ISSN 1433-7851
Abstract
DNAJB6 is a prime example of an anti-aggregation chaperone that functions as an oligomer. DNAJB6 oligomers are dynamic and subunit exchange is critical for inhibiting client protein aggregation. The T193A mutation in the C-terminal domain (CTD) of DNAJB6 reduces both chaperone self-oligomerization and anti-aggregation of client proteins, and has recently been linked to Parkinson's disease. Here, we show by NMR, including relaxation-based methods, that the T193A mutation has minimal effects on the structure of the β-stranded CTD but increases the population and rate of formation of a partially folded state. The results can be rationalized in terms of β-strand peptide plane flips that occur on a timescale of ≈100 μs and lead to global changes in the overall pleat/flatness of the CTD, thereby altering its ability to oligomerize. These findings help forge a link between chaperone dynamics, oligomerization and anti-aggregation activity which may possibly lead to new therapeutic avenues tuned to target specific substrates.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Hsp40 Chaperones; Oligomerization; Protein Correlated Motions; Protein Dynamics; Protein Excited States; Relaxation-Based NMR |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 223268/Z/21/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 28 Mar 2022 11:52 |
Last Modified: | 25 Jun 2023 22:56 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/anie.202116403 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:185080 |