Switching Demethylation Activities between AlkB Family RNA/DNA Demethylases through Exchange of Active-Site Residues†
Chenxu Zhu
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)
Search for more papers by this authorCorresponding Author
Prof. Chengqi Yi
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)Search for more papers by this authorChenxu Zhu
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)
Search for more papers by this authorCorresponding Author
Prof. Chengqi Yi
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)
State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Synthetic and Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871 (China)Search for more papers by this authorThis work was supported by the National Natural Science Foundation of China (No. 31270838) and the National Basic Research Foundation of China (No. 2014CB964900). We also thank the Shanghai Synchrotron Radiation Facility (BL17U) and Dr. F. Yu for assistance with X-ray data collection.
Abstract
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.
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