Structural analysis of the reversible self-assembly mechanism by intrinsically disordered proteins

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K06584
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43040:Biophysics-related
• Research Institution: Kyoto University
• Principal Investigator: Sekiyama Naotaka 京都大学, 理学研究科, 助教 (50758810)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 液-液相分離 / 天然変性タンパク質 / 神経変性疾患

Outline of Final Research Achievements

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 TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM) have been identified. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of PLD are synergistically determined by the physicochemical properties of amino acids. Molecular dynamics simulations and 3D electron crystallography together with biochemical assays revealed that the ALS mutations P362L and A381T enhanced the self-assembly by inducing b-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of pathogenic amyloid fibrillization following phase-separated droplet formation.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

TIA-1 PLDの構造学的研究により、神経変性疾患に関連するアミノ酸変異の影響が明らかになった。TIA-1は、何百種類ものタンパク質から構成されるストレス顆粒の中心的な役割を担っている。この事実は、TIA-1による自己組織化の破綻が、他のストレス顆粒構成因子との相互作用ネットワークを破壊し、不可逆凝集さらには神経変性疾患発症の発端になる可能性を示唆する。今回のTIA-1 PLDに関する詳細な構造学的知見により、筋萎縮性側索硬化症（ALS）などの神経変性疾患の発症メカニズムの解明につながることが期待される。