Switching Demethylation Activities between AlkB Family RNA/DNA Demethylases through Exchange of Active-Site Residues

被引:57
作者
Zhu, Chenxu [1 ,2 ]
Yi, Chengqi [1 ,2 ]
机构
[1] Peking Univ, Sch Life Sci, State Key Lab Prot & Plant Gene Res, Synthet & Funct Biomol Ctr, Beijing 100871, Peoples R China
[2] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China
基金
中国国家自然科学基金;
关键词
protein structures; RNA recognition; RNA/DNA demethylases; selective inhibition; substrate specificity; OBESITY-ASSOCIATED FTO; DNA ALKYLATION DAMAGE; REPAIR ENZYME ALKB; OXIDATIVE DEMETHYLATION; ESCHERICHIA-COLI; SUBSTRATE-SPECIFICITY; CRYSTAL-STRUCTURES; RNA DEMETHYLASE; ADULT OBESITY; MESSENGER-RNA;
D O I
10.1002/anie.201310050
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The AlkB family demethylases AlkB, FTO, and ALKBH5 recognize differentially methylated RNA/DNA substrates, which results in their distinct biological roles. Here we identify key active-site residues that contribute to their substrate specificity. Swapping such active-site residues between the demethylases leads to partially switched demethylation activities. Combined evidence from X-ray structures and enzyme kinetics suggests a role of the active-site residues in substrate recognition. Such a divergent active-site sequence may aid the design of selective inhibitors that can discriminate these homologue RNA/DNA demethylases.
引用
收藏
页码:3659 / 3662
页数:4
相关论文
共 38 条
[1]   Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA [J].
Aas, PA ;
Otterlei, M ;
Falnes, PO ;
Vågbo, CB ;
Skorpen, F ;
Akbari, M ;
Sundheim, O ;
Bjorås, M ;
Slupphaug, G ;
Seeberg, E ;
Krokan, HE .
NATURE, 2003, 421 (6925) :859-863
[2]   Structural Basis for Inhibition of the Fat Mass and Obesity Associated Protein (FTO) [J].
Aik, WeiShen ;
Demetriades, Marina ;
Hamdan, Muhammad K. K. ;
Bagg, Eleanor. A. L. ;
Yeoh, Kar Kheng ;
Lejeune, Clarisse ;
Zhang, Zhihong ;
McDonough, Michael A. ;
Schofield, Christopher J. .
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (09) :3680-3688
[3]   Development of Cell-Active N6-Methyladenosine RNA Demethylase FTO Inhibitor [J].
Chen, Baoen ;
Ye, Fei ;
Yu, Lu ;
Jia, Guifang ;
Huang, Xiaotian ;
Zhang, Xueju ;
Peng, Shuying ;
Chen, Kai ;
Wang, Meining ;
Gong, Shouze ;
Zhang, Ruihan ;
Yin, Jinya ;
Li, Haiyan ;
Yang, Yiming ;
Liu, Hong ;
Zhang, Jiwen ;
Zhang, Haiyan ;
Zhang, Ao ;
Jiang, Hualiang ;
Luo, Cheng ;
Yang, Cai-Guang .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2012, 134 (43) :17963-17971
[4]   Overexpression of Fto leads to increased food intake and results in obesity [J].
Church, Chris ;
Moir, Lee ;
McMurray, Fiona ;
Girard, Christophe ;
Banks, Gareth T. ;
Teboul, Lydia ;
Wells, Sara ;
Bruening, Jens C. ;
Nolan, Patrick M. ;
Ashcroft, Frances M. ;
Cox, Roger D. .
NATURE GENETICS, 2010, 42 (12) :1086-U147
[5]   DNA Unwinding by ASCC3 Helicase Is Coupled to ALKBH3-Dependent DNA Alkylation Repair and Cancer Cell Proliferation [J].
Dango, Sebastian ;
Mosammaparast, Nima ;
Sowa, Mathew E. ;
Xiong, Li-Jun ;
Wu, Feizhen ;
Park, Keyjung ;
Rubin, Mark ;
Gygi, Steve ;
Harper, J. Wade ;
Shi, Yang .
MOLECULAR CELL, 2011, 44 (03) :373-384
[6]   Variation in FTO contributes to childhood obesity and severe adult obesity [J].
Dina, Christian ;
Meyre, David ;
Gallina, Sophie ;
Durand, Emmanuelle ;
Koerner, Antje ;
Jacobson, Peter ;
Carlsson, Lena M. S. ;
Kiess, Wieland ;
Vatin, Vincent ;
Lecoeur, Cecile ;
Delplanque, Jerome ;
Vaillant, Emmanuel ;
Pattou, Francois ;
Ruiz, Juan ;
Weill, Jacques ;
Levy-Marchal, Claire ;
Horber, Fritz ;
Potoczna, Natascha ;
Hercberg, Serge ;
Le Stunff, Catherine ;
Bougneres, Pierre ;
Kovacs, Peter ;
Marre, Michel ;
Balkau, Beverley ;
Cauchi, Stephane ;
Chevre, Jean-Claude ;
Froguel, Philippe .
NATURE GENETICS, 2007, 39 (06) :724-726
[7]   Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq [J].
Dominissini, Dan ;
Moshitch-Moshkovitz, Sharon ;
Schwartz, Schraga ;
Salmon-Divon, Mali ;
Ungar, Lior ;
Osenberg, Sivan ;
Cesarkas, Karen ;
Jacob-Hirsch, Jasmine ;
Amariglio, Ninette ;
Kupiec, Martin ;
Sorek, Rotem ;
Rechavi, Gideon .
NATURE, 2012, 485 (7397) :201-U84
[8]   Alkylation damage in DNA and RNA -: repair mechanisms and medical significance [J].
Drablos, F ;
Feyzi, E ;
Aas, PA ;
Vaagbo, CB ;
Kavli, B ;
Bratlie, MS ;
Peña-Diaz, J ;
Otterlei, M ;
Slupphaug, G ;
Krokan, HE .
DNA REPAIR, 2004, 3 (11) :1389-1407
[9]   Reversal of DNA alkylation damage by two human dioxygenases [J].
Duncan, T ;
Trewick, SC ;
Koivisto, P ;
Bates, PA ;
Lindahl, T ;
Sedgwick, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (26) :16660-16665
[10]   AlkB-mediated oxidative demethylation reverses DNA damage in Escherichia coli [J].
Falnes, PO ;
Johansen, RF ;
Seeberg, E .
NATURE, 2002, 419 (6903) :178-182