Martin, EM, Jackson, MP orcid.org/0000-0002-4416-3499, Gamerdinger, M orcid.org/0000-0003-1483-8181 et al. (6 more authors) (2018) Conformational flexibility within the nascent polypeptide–associated complex enables its interactions with structurally diverse client proteins. Journal of Biological Chemistry, 293 (22). pp. 8554-8568. ISSN 0021-9258
Abstract
As newly synthesized polypeptides emerge from the ribosome, it is crucial that they fold correctly. To prevent premature aggregation, nascent chains interact with chaperones that facilitate folding or prevent misfolding until protein synthesis is complete. Nascent polypeptide–associated complex (NAC) is a ribosome-associated chaperone important for protein homeostasis. However, how NAC binds its substrates remains unclear. Using native electrospray ionization MS (ESI MS), limited proteolysis, NMR and cross-linking, we analysed the conformational properties of NAC from Caenorhabditis elegans and studied its ability to bind proteins in different conformational states. Our results revealed that NAC adopts an array of compact and expanded conformations and binds weakly to client proteins that are unfolded, folded, or intrinsically disordered, suggestive of broad substrate compatibility. Of note, we found that this weak binding retards aggregation of the intrinsically disordered protein α-synuclein both in vitro and in vivo. These findings provide critical insights into the structure and function of NAC. Specifically, they reveal the ability of NAC to exploit its conformational plasticity to bind a repertoire of substrates having unrelated sequences and structures independently of actively translating ribosomes.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2018 by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the terms of the Creative Commons Attribution License (CC BY 4.0). A copy of the license can be found at: https://creativecommons.org/licenses/by/4.0/ |
Keywords: | NAC; protein folding; molecular chaperone; protein cross-linking; chaperone protein misfolding |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Biomolecular Mass Spectroscopy (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Structural Molecular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Apr 2018 15:35 |
Last Modified: | 16 Dec 2024 13:42 |
Status: | Published |
Publisher: | American Society for Biochemistry and Molecular Biology |
Identification Number: | 10.1074/jbc.RA117.001568 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:129595 |