Substrate Specificity of the HEMK2 Protein Glutamine Methyltransferase and Identification of Novel Substrates.

The Journal of Biological Chemistry
Denis KusevicAlbert Jeltsch

Abstract

Bacterial HEMK2 homologs initially had been proposed to be involved in heme biogenesis or to function as adenine DNA methyltransferase. Later it was shown that this family of enzymes has protein glutamine methyltransferase activity, and they methylate the glutamine residue in the GGQ motif of ribosomal translation termination factors. The murine HEMK2 enzyme methylates Gln(185) of the eukaryotic translation termination factor eRF1. We have employed peptide array libraries to investigate the peptide sequence recognition specificity of murine HEMK2. Our data show that HEMK2 requires a GQX3R motif for methylation activity. In addition, amino acid preferences were observed between the -3 and +7 positions of the peptide substrate (considering the target glutamine as 0), including a preference for Ser, Arg, and Gly at the +1 and a preference for Arg at the +7 position. Based on our specificity profile, we identified several human proteins that contain putative HEMK2 methylation sites and show that HEMK2 methylates 58 novel peptide substrates. After cloning, expression, and purification of the corresponding protein domains, we confirmed methylation for 11 of them at the protein level. Transfected CHD5 (chromodomain helicase DNA-bindin...Continue Reading

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Citations

May 15, 2016·FEBS Letters·Maren Kirstin SchuhmacherAlbert Jeltsch
Jan 26, 2018·G3 : Genes - Genomes - Genetics·Sarah K NordquistJonathan T Pierce
May 8, 2019·Nature Structural & Molecular Biology·Eric MetzgerRoland Schüle
Sep 25, 2020·The Biochemical Journal·Jie GaoZhongliang Zhu
Jan 21, 2021·Nature Reviews. Drug Discovery·Kamakoti P BhatOr Gozani
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Mar 20, 2020·Current Protein & Peptide Science·Sebastian Kwiatkowski, Jakub Drozak
Aug 30, 2018·Journal of Proteome Research·Joshua J HameyMarc R Wilkins

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