Structural basis of regulated m7G tRNA modification by METTL1-WDR4

被引:58
作者
Li, Jiazhi [1 ,2 ,3 ]
Wang, Longfei [2 ,4 ,5 ]
Hahn, Quentin [1 ]
Nowak, Radoslaw P. [2 ,3 ]
Viennet, Thibault [2 ,3 ]
Orellana, Esteban A. [1 ,2 ]
Roy Burman, Shourya S. [2 ,3 ]
Yue, Hong [2 ,3 ]
Hunkeler, Moritz [2 ,3 ]
Fontana, Pietro [2 ,4 ]
Wu, Hao [2 ,4 ]
Arthanari, Haribabu [2 ,3 ]
Fischer, Eric S. [2 ,3 ]
Gregory, Richard I. [1 ,2 ,6 ,7 ,8 ,9 ]
机构
[1] Boston Childrens Hosp, Stem Cell Program, Div Hematol Oncol, Boston, MA 02115 USA
[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA USA
[4] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA
[5] Wuhan Univ, Sch Pharmaceut Sci, Wuhan, Peoples R China
[6] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA
[7] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA
[8] Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[9] Harvard Initiat RNA Med, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
BEAM-INDUCED MOTION; RAPID TRANSFER-RNA; GENE-EXPRESSION; RECONSTRUCTION; TRANSLATION; RESOLUTION; DECAY;
D O I
10.1038/s41586-022-05566-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Chemical modifications of RNA have key roles in many biological processes(1-3). N-7-methylguanosine (m(7)G) is required for integrity and stability of a large subset of tRNAs(4-7). The methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex is the methyltransferase that modifies G46 in the variable loop of certain tRNAs, and its dysregulation drives tumorigenesis in numerous cancer types(8-14). Mutations in WDR4 cause human developmental phenotypes including microcephaly(15-17). How METTL1-WDR4 modifies tRNA substrates and is regulated remains elusive(18). Here we show, through structural, biochemical and cellular studies of human METTL1-WDR4, that WDR4 serves as a scaffold for METTL1 and the tRNA T-arm. Upon tRNA binding, the alpha C region of METTL1 transforms into a helix, which together with the alpha 6 helix secures both ends of the tRNA variable loop. Unexpectedly, we find that the predicted disordered N-terminal region of METTL1 is part of the catalytic pocket and essential for methyltransferase activity. Furthermore, we reveal that S27 phosphorylation in the METTL1 N-terminal region inhibits methyltransferase activity by locally disrupting the catalytic centre. Our results provide a molecular understanding of tRNA substrate recognition and phosphorylation-mediated regulation of METTL1-WDR4, and reveal the presumed disordered N-terminal region of METTL1 as a nexus of methyltransferase activity.
引用
收藏
页码:391 / +
页数:22
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