METTL9 mediated N1-histidine methylation of zinc transporters is required for tumor growth

Enzymology and significance of protein histidine methylation

“…Davydova et al recently uncovered METTL9 as the first 1MeH specific enzyme, and third human PHMT, using a wide range of biochemical and cellular assays (59), and this finding has been independently validated (60). The enzyme was shown to catalyse the generation of 1MeH in the C-terminal histidine residue of a linear sequence motifs corresponding to HxH, where "x" represents a small amino acid such as alanine, asparagine, glycine, serine or threonine.…”

siRNA screening identifies METTL9 as a histidine Nπ-methyltransferase that targets the proinflammatory protein S100A9

“…Thereafter, Lv et al . ( 25 ) also provided evidence for METTL9-mediated N p-methylhistidine formation and confirmed that METTL9 recognizes an x-His-x-His motif in the substrate protein. However, while their focuses were on METTL9 as one of the uncharacterized mammalian 7BS MTases, our present work set out to identify the enzymes responsible for histidine N p-methylation of S100A9 by using an unbiased siRNA screen ( Fig.…”

The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

“…Indeed, it was recently found that METTL9 methyltransferase acts as a broad specificity enzyme, catalyzing the formation of the majority of Nπ-methylhistidine residues in the human proteome, including S100A9 and NDUFB3 proteins [19]. This was also confirmed by Lv and colleagues, who established that METTL9 recognizes an xHxH motif in substrate proteins [20], whereas proteomic studies indicated that the motif is mainly present in human proteins that are methylated at histidine residues [21]. Moreover, the human METTL18 enzyme was shown to Nτ-methylate histidine 245 in ribosomal protein RPL3 [22,23], and, thus, resembles its yeast homolog HPM1 protein [7,24].…”