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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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Yu-Teng Zeng Lu-Lu Bi Xiao-Feng Zhuo Ling-Yun Yang Bo Sun Jun-Xia Lu |
| author_facet | Yu-Teng Zeng Lu-Lu Bi Xiao-Feng Zhuo Ling-Yun Yang Bo Sun Jun-Xia Lu |
| author_sort | Yu-Teng Zeng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T17:44:14Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:44:14Z |
| publishDate | 2022-12-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-22685f9033ce4c9eb1500bfb99fe278d2023-11-24T11:15:25ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123231522710.3390/ijms232315227Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43Yu-Teng Zeng0Lu-Lu Bi1Xiao-Feng Zhuo2Ling-Yun Yang3Bo Sun4Jun-Xia Lu5School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaiHuman Institute, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaThe 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.https://www.mdpi.com/1422-0067/23/23/15227TDP-43liquid–liquid phase separationsolution-state NMR |
| spellingShingle | Yu-Teng Zeng Lu-Lu Bi Xiao-Feng Zhuo Ling-Yun Yang Bo Sun Jun-Xia Lu Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43 International Journal of Molecular Sciences TDP-43 liquid–liquid phase separation solution-state NMR |
| 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 | TDP-43 liquid–liquid phase separation solution-state NMR |
| url | https://www.mdpi.com/1422-0067/23/23/15227 |
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