Structural dynamics of tumor suppressor protein, p53, in its aggregation process

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06521
• 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: Kanazawa University
• Principal Investigator: Takahiro Nakayama 金沢大学, ナノ生命科学研究所, 准教授 (00532821)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: がん抑制因子 / タンパク凝集 / 一分子観察

Outline of Final Research Achievements

The tumor suppressor protein, p53, is the protein most frequently found mutated in cancer, and it is well established that expression of the mutant form induces loss of tumor-suppressing function of the wild type by a dominant-negative effect. However, the molecular mechanism of this dominant-negative effect is unknown because p53 contains intrinsically disordered regions and its full-length structure cannot be determined by conventional structural analysis. In this study, we observed p53 using high-speed atomic force microscopy, which can visualize the structural dynamics of intrinsically disordered proteins including amyloidogenic proteins. As a result, we found that the core domain (DNA binding domain) of p53 forms a protofibril-like structure under physiological conditions, which is defined as the precursors of amyloid fibrils.

Free Research Field

生物物理化学

Academic Significance and Societal Importance of the Research Achievements

本研究では、p53が凝集してアミロイド特有のクロスβ構造を持ち得ることを示した。さらに、液中生理条件下における試料の3次元構造がアミロイド線維というよりもむしろアミロイド線維前駆体であるプロトフィブリルに似た構造であることを発見した。近年、神経変性疾患の分野では、アミロイド線維よりもオリゴマーやプロトフィブリルの方が毒性が高いことが定説になりつつある。今後、細胞・組織レベルにおけるp53プロトフィブリル様凝集体の機能解析を進めることで、本研究成果は、p53変異による腫瘍発生メカニズムに新たなコンセプトを提供し得る。