Ubiquitin structural biology providing the molecular basis for chemo-technologies

2022 Fiscal Year Final Research Report

• Project Area: New frontier for ubiquitin biology driven by chemo-technologies
• Project/Area Number: 18H05501
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: Kyoto University (2020-2022); The University of Tokyo (2018-2019)
• Principal Investigator: Fukai Shuya 京都大学, 理学研究科, 教授 (10361792)
• Project Period (FY): 2018-06-29 – 2023-03-31
• Keywords: 構造生物学 / 分子間相互作用 / ユビキチン / シグナル伝達 / タンパク質工学 / ケミカルバイオロジー / X線結晶構造解析

Outline of Final Research Achievements

The ubiquitin modification, which was originally identified as a signal for protein degradation, is now known to play an essential role in the regulation of diverse cellular functions. Ubiquitin chains formed by covalently linking ubiquitin molecules are closely associated with the diversity of functions. Research aimed at understanding the molecular mechanisms of attachment, recognition, and removal of ubiquitin chains and artificially controlling cellular functions could contribute to therapeutic development for various diseases. In this study, we determined the three-dimensional structures of protein complexes associated with the ubiquitin chain modification to deepen the understanding of novel ubiquitin chain recognition mechanisms and molecular mechanisms involving ubiquitin chains. Furthermore, based on the obtained structural information, we attempted to design compounds that could control the function.

Free Research Field

構造生物化学

Academic Significance and Societal Importance of the Research Achievements

ユビキチン鎖と結合タンパク質の複合体（Npl4-K48鎖やTab2-K6鎖など）の立体構造解析によって新たなユビキチン鎖認識機構を明らかにした。また、ユビキチンリガーゼLUBACの触媒サブユニットHOIPの阻害剤HOIPINやUSPファミリーの脱ユビキチン化酵素を阻害する化合物Subquinocinといったユビキチン鎖が関与するタンパク質に結合する化合物の作用メカニズムを立体構造に基づいて理解し、共同研究も含めて原子・分子レベルから細胞・個体レベルまでの解析通じて免疫疾患に対する新たな治療法の可能性を示した。