Structural basis for substrate binding and catalytic mechanism of a human RNA:m5C methyltransferase NSun6

Nucleic Acids Research
Ru-Juan LiuEn-Duo Wang

Abstract

5-methylcytosine (m5C) modifications of RNA are ubiquitous in nature and play important roles in many biological processes such as protein translational regulation, RNA processing and stress response. Aberrant expressions of RNA:m5C methyltransferases are closely associated with various human diseases including cancers. However, no structural information for RNA-bound RNA:m5C methyltransferase was available until now, hindering elucidation of the catalytic mechanism behind RNA:m5C methylation. Here, we have solved the structures of NSun6, a human tRNA:m5C methyltransferase, in the apo form and in complex with a full-length tRNA substrate. These structures show a non-canonical conformation of the bound tRNA, rendering the base moiety of the target cytosine accessible to the enzyme for methylation. Further biochemical assays reveal the critical, but distinct, roles of two conserved cysteine residues for the RNA:m5C methylation. Collectively, for the first time, we have solved the complex structure of a RNA:m5C methyltransferase and addressed the catalytic mechanism of the RNA:m5C methyltransferase family, which may allow for structure-based drug design toward RNA:m5C methyltransferase-related diseases.

References

Jan 1, 1994·Biochimie·J T KealeyD V Santi
Jul 19, 2000·Proceedings of the National Academy of Sciences of the United States of America·Y Liu, D V Santi
Sep 15, 2001·Nucleic Acids Research·X Cheng, R J Roberts
Jun 20, 2002·Human Genetics·Giuseppe MerlaAlexandre Reymond
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jan 3, 2006·Molecular Cell·Andrei AlexandrovEric M Phizicky
Jan 13, 2006·The Journal of Biological Chemistry·Jeffrey Sabina, Dieter Söll
Jan 21, 2006·Science·Mary Grace GollTimothy H Bestor
May 9, 2006·Journal of Molecular Biology·Niels Møller Andersen, Stephen Douthwaite
Sep 1, 2006·Nature·Ling Li, Keqiong Ye
Mar 14, 2007·Nature Structural & Molecular Biology·Ryuya Fukunaga, Shigeyuki Yokoyama
May 2, 2007·The Journal of Biological Chemistry·Sylvie AuxilienHenri Grosjean
Sep 7, 2007·The FEBS Journal·Isabel Pérez-ArellanoJavier Cervera
May 3, 2008·Proceedings of the National Academy of Sciences of the United States of America·Akram AlianJanet Finer-Moore
Sep 13, 2008·Journal of Molecular Biology·Elzbieta PurtaStephen Douthwaite
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Dec 17, 2009·Nucleic Acids Research·Yuri MotorinMark Helm
Jul 6, 2010·Journal of Molecular Biology·Mitsuo KurataniShigeyuki Yokoyama
Nov 13, 2010·Nucleic Acids Research·William A CantaraPaul F Agris
Dec 3, 2010·Acta Crystallographica. Section D, Biological Crystallography·Yasushi HikidaShigeyuki Yokoyama
Feb 22, 2012·Nucleic Acids Research·Jeffrey E SquiresThomas Preiss
May 1, 2012·American Journal of Human Genetics·Lia Abbasi-MohebAndreas W Kuss
May 1, 2012·American Journal of Human Genetics·Muzammil Ahmad KhanJohn B Vincent
May 12, 2012·Journal of Medical Genetics·Fernando Jose MartinezJoseph G Gleeson
Aug 14, 2012·Nature Structural & Molecular Biology·Francesca TuortoFrank Lyko
Sep 6, 2012·Proceedings of the National Academy of Sciences of the United States of America·Henrik SpåhrB Martin Hallberg

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Citations

May 19, 2018·Nature Reviews. Drug Discovery·P Ann Boriack-SjodinRobert A Copeland
Oct 13, 2018·Wiley Interdisciplinary Reviews. RNA·Lukas Trixl, Alexandra Lusser
Dec 13, 2018·Nucleic Acids Research·Jing LiRu-Juan Liu
Jun 26, 2020·Cell Death & Disease·Weifeng YaoZiqing Hei
Sep 17, 2019·Biochemistry. Biokhimii︠a︡·S A KuznetsovaO A Dontsova
Nov 5, 2020·International Journal of Molecular Sciences·Maciej WnukAnna Lewinska
Dec 18, 2020·Nucleic Acids Research·Tommaso SelmiMichaela Frye
Dec 29, 2020·Frontiers in Molecular Biosciences·Shixin XiangZhangang Xiao
Jan 14, 2021·Wiley Interdisciplinary Reviews. RNA·Yu-Sheng ChenYun-Gui Yang
Apr 1, 2021·Expert Reviews in Molecular Medicine·Xiaofeng DaiNan Nan
Apr 22, 2021·Science China. Life Sciences·Jing LiRu-Juan Liu
May 22, 2021·Cancer Research·Santanu AdhikaryChandrima Das
Oct 19, 2019·Journal of the American Chemical Society·Tyler S SmithMatthew D Simon
Dec 7, 2021·Nucleic Acids Research·Zhi-Xuan HuangRu-Juan Liu

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Methods Mentioned

BETA
isothermal titration calorimetry
electrophoresis

Software Mentioned

Origin
CCP4 suite
ESPript
COOT
PHASER
PHENIX suite
REFINE

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