Deciphering the molecular mechanism of liquid-liquid phase separation from low-complexity sequences that vary by species

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K06525
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Tokyo Institute of Technology (2023); Kobe University (2020-2022)
• Principal Investigator: Ohhashi Yumiko 東京工業大学, 科学技術創成研究院, 特任講師 (10422669)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 液-液相分離 / アミロイド / 天然変性蛋白質

Outline of Final Research Achievements

We researched to elucidate how amyloid formation from phase-separated droplets is suppressed. The N-terminal region of the Sup35 protein (Sup35NM) has a different sequence depending on the yeast species. By mixing these proteins, we constructed an in vitro system where multiple proteins coexist, mimicking the environment of intracellular conditions.
It was found that the four types of Sup35NM can coexist within the droplets and that their coexistence within the droplets delays amyloid formation. A protein with an amino acid composition similar to Sup35 colocalizes in the droplets within yeast cells, suggesting that amyloid formation is suppressed by a similar mechanism within the cells.

Free Research Field

タンパク質科学

Academic Significance and Societal Importance of the Research Achievements

タンパク質の異常凝集体であるアミロイドは、様々な重篤な疾患に関与しており、その多くは治療法が確立していない。そのため多方面から勢力的に研究が行われているが、どのようにして体内でアミロイドが形成されるのか、つまりアミロイド病発症のメカニズムは未解明である。相分離液滴からのアミロイド形成は近年発見された新たなアミロイド病発症モデルであり、その詳細な解析とアミロイド形成抑制機構の解明は今後の創薬や治療法開発の上で重要な知見となると期待できる。