ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures

筋萎縮性側索硬化症（ALS）の発症機構の一端を解明 --タンパク質の高密度な凝縮構造が鍵--. 京都大学プレスリリース. 2022-09-13.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

ユビキチンおよびユビキチン様蛋白質受容体の構造学的研究

京都大学0048新制・課程博士博士(工学)甲第15395号工博第3274号新制||工||1493(附属図書館)27873京都大学大学院工学研究科分子工学専攻(主査)教授 白川 昌宏, 教授 梶 弘典, 教授 森 泰生学位規則第4条第1項該当Doctor of Philosophy (Engineering)Kyoto UniversityDA