Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan.
Biostructural Mechanism Laboratory, RIKEN SPring-8 Center, Sayo 679-5148, Japan.
Proc Natl Acad Sci U S A. 2022 Sep 20;119(38):e2122523119. doi: 10.1073/pnas.2122523119. Epub 2022 Sep 16.
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.
T 细胞内抗原-1（TIA-1）通过其类朊样结构域（PLD）自组装在应激颗粒（SG）形成中发挥核心作用。在 TIA-1 PLD 中，已经鉴定出与神经退行性疾病（如肌萎缩侧索硬化症（ALS）或 Welander 远端肌病（WDM）相关的氨基酸突变。然而，这些突变如何影响 PLD 自组装特性仍然难以捉摸。在这项研究中，我们揭示了突变引起的潜在致病结构。NMR 分析表明，PLD 的动态结构是由五个残基单位的氨基酸的物理化学性质协同决定的。分子动力学模拟和三维电子晶体学以及生化分析表明，WDM 突变 E384K 降低了粘性特性，而 ALS 突变 P362L 和 A381T 分别通过诱导β-折叠相互作用和高度浓缩组装增强了自组装。这些结果表明，P362L 和 A381T 突变增加了相分离液滴形成后不可逆淀粉样纤维形成的可能性，并且该过程可能导致致病性。
