Ruff, KM, Choi, YH, Cox, D et al. (6 more authors) (2022) Sequence grammar underlying the unfolding and phase separation of globular proteins. Molecular Cell, 82 (17). 3193-3208.e8. ISSN 1097-2765
Abstract
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
Keywords: | proteostasis; protein quality control; protein folding; protein misfolding; barnase; molecular condensate; protein deposit; Cry2; chaperonin-containing T-complex; TRiC; superoxide dismutase 1; SOD1 |
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) > Structural Molecular Biology (Leeds) |
Funding Information: | Funder Grant number Wellcome Trust 204963/Z/16/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 14 Jun 2022 12:41 |
Last Modified: | 01 Mar 2023 10:38 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.molcel.2022.06.024 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:187900 |