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Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43

The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the...

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Autores principales: Zeng, Yu-Teng, Bi, Lu-Lu, Zhuo, Xiao-Feng, Yang, Ling-Yun, Sun, Bo, Lu, Jun-Xia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741235/
https://www.ncbi.nlm.nih.gov/pubmed/36499553
http://dx.doi.org/10.3390/ijms232315227
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author Zeng, Yu-Teng
Bi, Lu-Lu
Zhuo, Xiao-Feng
Yang, Ling-Yun
Sun, Bo
Lu, Jun-Xia
author_facet Zeng, Yu-Teng
Bi, Lu-Lu
Zhuo, Xiao-Feng
Yang, Ling-Yun
Sun, Bo
Lu, Jun-Xia
author_sort Zeng, Yu-Teng
collection PubMed
description The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.
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spelling pubmed-97412352022-12-11 Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43 Zeng, Yu-Teng Bi, Lu-Lu Zhuo, Xiao-Feng Yang, Ling-Yun Sun, Bo Lu, Jun-Xia Int J Mol Sci Article The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD. MDPI 2022-12-03 /pmc/articles/PMC9741235/ /pubmed/36499553 http://dx.doi.org/10.3390/ijms232315227 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zeng, Yu-Teng
Bi, Lu-Lu
Zhuo, Xiao-Feng
Yang, Ling-Yun
Sun, Bo
Lu, Jun-Xia
Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title_full Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title_fullStr Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title_full_unstemmed Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title_short Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43
title_sort different intermolecular interactions drive nonpathogenic liquid–liquid phase separation and potentially pathogenic fibril formation by tdp-43
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741235/
https://www.ncbi.nlm.nih.gov/pubmed/36499553
http://dx.doi.org/10.3390/ijms232315227
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