New publication in "Protein Science"

New publication in "Proten Science"

The HEMK2 protein methyltransferase has been described as glutamine (Q) methyltransferase catalyzing ERF1-Q185me1 and lysine (K) methyltransferase catalyzing H4K12me1. Methylation of two distinct target residues is unique for this class of enzymes. To understand the specific catalytic adaptations of HEMK2 allowing it to master this chemically challenging task, we conducted a detailed investigation of the substrate sequence specificities of HEMK2 for Q- and K-methylation. Our data show that HEMK2 prefers methylation of Q and it strongly prefers the ERF1 sequence context over H4K12. We show that Q-methylation preferentially occurs in a G- Q-X ₃-R context while K-methylation prefers S/T at the first position of the motif. Based on this, we identified novel HEMK2 K-methylation substrates which are strongly methylated. Since H4K12 methylation by HEMK2 was very low, other protein lysine methyltransferases were examined for their ability to methylate the H4K12 site. We show that SETD6 has a high H4K12me1 methylation activity (about 1000-times stronger than HEMK2) and this enzyme is mainly responsible for H4K12me1 in prostate cancer cells.