ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures
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- 関山, 直孝
- Department of Biophysics, Graduate School of Science, Kyoto University
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- 高場, 圭章
- Biostructural Mechanism Laboratory, RIKEN SPring-8 Center
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- 眞木, さおり
- Biostructural Mechanism Laboratory, RIKEN SPring-8 Center
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- 赤木, 謙一
- Section of Laboratory Equipment, National Institute of Biomedical Innovation, Health, and Nutrition; Present address: Environmental Metabolic Analysis Research Team, RIKEN Center for Sustainable Resource Science
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- 大谷, 寧子
- Department of Biophysics, Graduate School of Science, Kyoto University
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- 今村, 香代
- Department of Biophysics, Graduate School of Science, Kyoto University
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- 寺川, 剛
- Department of Biophysics, Graduate School of Science, Kyoto University
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- 山下, 恵太郎
- Structural Studies Division, Medical Research Council Laboratory of Molecular Biology
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- 稲岡, 大悟
- Department of Biophysics, Graduate School of Science, Kyoto University
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- 米倉, 功治
- Biostructural Mechanism Laboratory, RIKEN SPring-8 Center; Institute of Multidisciplinary Research for Advanced Materials, Tohoku University; Advanced Electron Microscope Development Unit, RIKEN-JEOL Collaboration Center, RIKEN Baton Zone Program
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- 児玉, 高志
- Department of Biophysics, Graduate School of Science, Kyoto University; Present address: Institute for Protein Research, Osaka University
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- 杤尾, 豪人
- Department of Biophysics, Graduate School of Science, Kyoto University
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説明
T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity.
収録刊行物
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- Proceedings of the National Academy of Sciences (PNAS)
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Proceedings of the National Academy of Sciences (PNAS) 119 (38), 1-, 2022-09-20
National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1050858441648025216
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- ISSN
- 10916490
- 00278424
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- HANDLE
- 2433/279869
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- PubMed
- 36112647
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- 本文言語コード
- en
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- 資料種別
- journal article
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- データソース種別
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- IRDB
- Crossref
- KAKEN
- OpenAIRE
