哺乳动物TRIM71蛋白RNA结合特性的分子机制研究（英文）

作     者：时凡迪 张坤 程玘轩 车世友 支树馨 郁珍瑜 刘飞 段菲菲 汪阳明 杨娜 

作者机构：State Key Laboratory of Medicinal Chemical Biology College of Pharmacy Nankai University Institute of Molecular Medicine College of Future Technology Peking University College of Chemistry Tianjin Normal University National Laboratory of Biomacromolecules and Key Laboratory of Epigenetic Regulation and Intervention Institute of Biophysics Chinese Academy of Sciences 

出 版 物：《Science Bulletin》 (科学通报(英文版))

年 卷 期：2024年第1期

页      面：72-81页

核心收录：

学科分类：0710[理学-生物学] 07[理学] 071007[理学-遗传学] 

基　　金：supported by the Chinese Ministry of Science and Technology,the National Natural Science Foundation of China(2019YFA0508902, 32170549, 32371315, 2021YFA1100200, and 91940302) Haihe Laboratory of Cell Ecosystem Innovation Fund (22HHXBSS00021) 

摘      要：TRIM71 is an RNA-binding protein with ubiquitin ligase activity. Numerous functions of mammalian TRIM71, including cell cycle regulation, embryonic stem cell(ESC) self-renewal, and reprogramming of pluripotent stem cells, are related to its RNA-binding property. We previously reported that a long noncoding RNA(lnc RNA) Trincr1 interacts with mouse TRIM71(m TRIM71) to repress FGF/ERK pathway in mouse ESCs(m ESCs). Herein, we identify an RNA motif specifically recognized by m TRIM71 from Trincr1 RNA, and solve the crystal structure of the NHL domain of m TRIM71 complexed with the RNA motif. Similar to the zebrafish TRIM71, m TRIM71 binds to a stem-loop structured RNA fragment of Trincr1, and an adenosine base at the loop region is crucial for the m TRIM71 interaction. We map similar hairpin RNAs preferably bound by TRIM71 in the m RNA UTRs of the cell-cycle related genes regulated by TRIM71. Furthermore, we identify key residues of m TRIM71, conserved among mammalian TRIM71 proteins, required for the RNA-binding property. Single-site mutations of these residues significantly impair the binding of TRIM71 to hairpin RNAs in vitro and to m RNAs of Cdkn1a/p21 and Rbl2/p130 in m ***, congenital hydrocephalus(CH) specific mutation of m TRIM71 impair its binding to the RNA targets as well. These results reveal molecular mechanism behind the recognition of RNA by mammalian TRIM71 and provide insights into TRIM71 related diseases.