Ministry of Education, Culture, Sports, Science and Technology (Japan)
JPMXS0421700121
日本
Japan Agency for Medical Research and Development (AMED)
日本
引用
ジャーナル: Proc Natl Acad Sci U S A / 年: 2022 タイトル: ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures. 著者: Naotaka Sekiyama / Kiyofumi Takaba / Saori Maki-Yonekura / Ken-Ichi Akagi / Yasuko Ohtani / Kayo Imamura / Tsuyoshi Terakawa / Keitaro Yamashita / Daigo Inaoka / Koji Yonekura / Takashi S ...著者: Naotaka Sekiyama / Kiyofumi Takaba / Saori Maki-Yonekura / Ken-Ichi Akagi / Yasuko Ohtani / Kayo Imamura / Tsuyoshi Terakawa / Keitaro Yamashita / Daigo Inaoka / Koji Yonekura / Takashi S Kodama / Hidehito Tochio / 要旨: 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 ...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.
履歴
登録
2021年9月24日
登録サイト: PDBJ / 処理サイト: PDBJ
改定 1.0
2022年9月28日
Provider: repository / タイプ: Initial release
改定 1.1
2024年6月19日
Group: Data collection / カテゴリ: chem_comp_atom / chem_comp_bond