Mechanism of the formation of a translational repression complex that plays a role in the proliferation of cancer and stem cells and molecular basis of drug discovery

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K07307
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Kyoto University
• Principal Investigator: Nagata Takashi 京都大学, エネルギー理工学研究所, 准教授 (10415250)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: Musashi / RNA / NMR / AFM

Outline of Final Research Achievements

Musashi1 (Msi1), which is involved in proliferative maintenance of cancer and stem cells, has two RNA-binding domains, RBD1 and RBD2. We firstly elucidated the driving force of how RBD1 recognizes the target RNA in highly specific manner by means of statistical mechanics of hydration. We also determined the NMR structure of the RBD2:target RNA complex, by which we elucidated the interaction mode. We then built a structural model of the Msi1 RBD1-RBD2:target RNA complex, and demonstrated that Msi1 can bind to the target RNAs having different lengths. As for FUS, a causal agent for neurodegenerative diseases, we demonstrated that it exhibits large conformational change upon target RNA binding.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

Msi1は種々の癌細胞において過剰発現しており創薬ターゲットである。本研究ではMsi1のRNA結合認識機構をミクロな視点で明らかにした。得られた知見と我々の方法論は、Msi1が標的RNAと結合するのを阻害する化合物のスクリーニング及び設計に役立てることが可能であり、既にスクリーニングにおいては活用されている。一方で、FUSの機能発現の理解につながる重要な知見をマクロな視点から得ることが出来た。