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Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch
An evolutionarily conserved region of the TDP-43 low-complexity domain (LCD) twenty residues in length can adopt either an α-helical or β-strand conformation. When in the latter conformation, TDP-43 self-associates via the formation of a labile, cross-β structure. Self-association can be monitored v...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576115/ https://www.ncbi.nlm.nih.gov/pubmed/37782781 http://dx.doi.org/10.1073/pnas.2311416120 |
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author | Gu, Jinge Zhou, Xiaoming Sutherland, Lillian Kato, Masato Jaczynska, Klaudia Rizo, Josep McKnight, Steven L. |
author_facet | Gu, Jinge Zhou, Xiaoming Sutherland, Lillian Kato, Masato Jaczynska, Klaudia Rizo, Josep McKnight, Steven L. |
author_sort | Gu, Jinge |
collection | PubMed |
description | An evolutionarily conserved region of the TDP-43 low-complexity domain (LCD) twenty residues in length can adopt either an α-helical or β-strand conformation. When in the latter conformation, TDP-43 self-associates via the formation of a labile, cross-β structure. Self-association can be monitored via the formation of phase-separated protein droplets. Exposure of droplets to hydrogen peroxide leads to oxidation of conserved methionine residues distributed throughout the LCD. Oxidation disassembles the cross-β structure, thus eliminating both self-association and phase separation. Here, we demonstrate that this process reciprocally enables formation of α-helical structure in precisely the same region formerly functioning to facilitate β-strand-mediated self-association. We further observe that the α-helical conformation allows interaction with a lipid-like detergent and that exposure to lipids enhances the β-to-α conformational switch. We hypothesize that regulation of this oxidative switch will prove to be important to the control of localized translation within vertebrate cells. The experimental observations reported herein were heavily reliant on studies of 1,6-hexanediol, a chemical agent that selectively dissolves labile structures formed via the self-association of protein domains of low sequence complexity. This aliphatic alcohol is shown to exert its dissociative activity primarily via hydrogen-bonding interactions with carbonyl oxygen atoms of the polypeptide backbone. Such observations underscore the central importance of backbone-mediated protein:protein interactions that facilitate the self-association and phase separation of LCDs. |
format | Online Article Text |
id | pubmed-10576115 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-105761152023-10-15 Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch Gu, Jinge Zhou, Xiaoming Sutherland, Lillian Kato, Masato Jaczynska, Klaudia Rizo, Josep McKnight, Steven L. Proc Natl Acad Sci U S A Biological Sciences An evolutionarily conserved region of the TDP-43 low-complexity domain (LCD) twenty residues in length can adopt either an α-helical or β-strand conformation. When in the latter conformation, TDP-43 self-associates via the formation of a labile, cross-β structure. Self-association can be monitored via the formation of phase-separated protein droplets. Exposure of droplets to hydrogen peroxide leads to oxidation of conserved methionine residues distributed throughout the LCD. Oxidation disassembles the cross-β structure, thus eliminating both self-association and phase separation. Here, we demonstrate that this process reciprocally enables formation of α-helical structure in precisely the same region formerly functioning to facilitate β-strand-mediated self-association. We further observe that the α-helical conformation allows interaction with a lipid-like detergent and that exposure to lipids enhances the β-to-α conformational switch. We hypothesize that regulation of this oxidative switch will prove to be important to the control of localized translation within vertebrate cells. The experimental observations reported herein were heavily reliant on studies of 1,6-hexanediol, a chemical agent that selectively dissolves labile structures formed via the self-association of protein domains of low sequence complexity. This aliphatic alcohol is shown to exert its dissociative activity primarily via hydrogen-bonding interactions with carbonyl oxygen atoms of the polypeptide backbone. Such observations underscore the central importance of backbone-mediated protein:protein interactions that facilitate the self-association and phase separation of LCDs. National Academy of Sciences 2023-10-02 2023-10-10 /pmc/articles/PMC10576115/ /pubmed/37782781 http://dx.doi.org/10.1073/pnas.2311416120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Gu, Jinge Zhou, Xiaoming Sutherland, Lillian Kato, Masato Jaczynska, Klaudia Rizo, Josep McKnight, Steven L. Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title | Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title_full | Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title_fullStr | Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title_full_unstemmed | Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title_short | Oxidative regulation of TDP-43 self-association by a β-to-α conformational switch |
title_sort | oxidative regulation of tdp-43 self-association by a β-to-α conformational switch |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576115/ https://www.ncbi.nlm.nih.gov/pubmed/37782781 http://dx.doi.org/10.1073/pnas.2311416120 |
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