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

  • Commun Biol. 2018 Nov 2;1:183. doi: 10.1038/s42003-018-0196-2.
Cheng Dong  1 ,  Guangping Dong  2 ,  Li Li  1 ,  Licheng Zhu  1  3 ,  Wolfram Tempel  1 ,  Yanli Liu  1 ,  Rong Huang  4 ,  Jinrong Min  5  6
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto, Toronto, M5G1L7, ON, Canada.
  • 2. Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA.
  • 3. School of Life Sciences, Jinggangshan University, 343009, Ji'an, Jiangxi, China.
  • 4. Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, Institute for Drug Discovery, Purdue University, West Lafayette, IN, 47907, USA. [email protected].
  • 5. Structural Genomics Consortium, University of Toronto, Toronto, M5G1L7, ON, Canada. [email protected].
  • 6. Department of Physiology, University of Toronto, Toronto, M5S 1A8, ON, Canada. [email protected].
PMID: 30417120 DOI: 10.1038/s42003-018-0196-2
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.