Dynamic Character of the Ubiquitin System

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K14665
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43040:Biophysics-related
• Research Institution: Kyoto University
• Principal Investigator: WALINDA ERIK 京都大学, 医学研究科, 助教 (80782391)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ubiquitin / ubiquitin binding / UBA domain / K48-linked chains / K63-linked chains / M1-linked chains / solution NMR / molecular dynamics

Outline of Final Research Achievements

In these two years, our research has proceeded rather smoothly. We could publish several results of this project in international peer-reviewed journals. For example, molecular dynamics simulations and NMR experiments on K48-, K63-, and M1-linked ubiquitin chains produced intriguing results that well agree with observations by other researchers worldwide, e.g. in the field of X-ray crystallography. Specifically, various distinct ubiquitin chain conformations of the same molecule (e.g., a K48-linked diubiquitin molecule) have been reported by different researchers under different crystallization conditions or in the presence of different binding proteins. However, we found that all of these molecular states of diubiquitin lie on the same trajectory in phase-space as sampled by molecular dynamics. The main result of this project is summarized in our 2021 Biochemistry paper. However, several aspects of this study (especially for chains other than K48-linked) are yet to be published.

Free Research Field

生物物理学

Academic Significance and Societal Importance of the Research Achievements

長年多くの病理学者たちが抱いてきた不思議は、神経変性疾患で観察される異常タンパク質凝集体（封入体）のほとんどにユビキチンが含まれていることである。どのようにしてポリユビキチン鎖が正しく認識されなくなり、凝集体を形成するかを原子分解能で解析したものであり、得られた研究成果は封入体の形成機構の理解、つまり神経変性疾患の発症機構の理解の一助となると考える。また、得られた構造学的情報は、熱や流体力学的応力によるマルチドメインタンパク質の構造変化や分子間相互作用を理解する上で重要な知見となり得ると考える。