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Commun Biol. 2018 Nov 2;1:183. doi: 10.1038/s42003-018-0196-2. eCollection 2018.

An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2.

Author information

1
1Structural Genomics Consortium, University of Toronto, Toronto, M5G1L7 ON Canada.
2
2Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907 USA.
3
3School of Life Sciences, Jinggangshan University, 343009 Ji'an, Jiangxi China.
4
4Department of Physiology, University of Toronto, Toronto, M5S 1A8 ON Canada.
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Contributed equally

Abstract

α-N-terminal methylation of proteins is an important post-translational modification that is catalyzed by two different N-terminal methyltransferases, namely NTMT1 and NTMT2. Previous studies have suggested that NTMT1 is a tri-methyltransferase, whereas NTMT2 is a mono-methyltransferase. Here, we report the first crystal structures, to our knowledge, of NTMT2 in binary complex with S-adenosyl-L-methionine as well as in ternary complex with S-adenosyl-L-homocysteine and a substrate peptide. Our structural observations combined with biochemical studies reveal that NTMT2 is also able to di-/tri-methylate the GPKRIA peptide and di-methylate the PPKRIA peptide, otherwise it is predominantly a mono-methyltransferase. The residue N89 of NTMT2 serves as a gatekeeper residue that regulates the binding of unmethylated versus monomethylated substrate peptide. Structural comparison of NTMT1 and NTMT2 prompts us to design a N89G mutant of NTMT2 that can profoundly alter its catalytic activities and product specificities.

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