# The Protein Histidine Methyltransferase METTL9—From Mechanism to Biological Function

## TL;DR

This review explores METTL9, an enzyme that methylates histidine in proteins, and its role in regulating protein function, particularly by affecting zinc binding.

## Contribution

The paper provides a comprehensive overview of METTL9's mechanism and biological functions, highlighting its role in modulating zinc-dependent proteins.

## Key findings

- METTL9 methylates histidine residues in proteins, primarily at HxH motifs.
- Histidine methylation by METTL9 reduces zinc binding in proteins like S100A9 and SLC39A7.
- The review details the biochemical and structural features of METTL9 and its substrates.

## Abstract

Proteins can be methylated at either of the two N atoms of the imidazole ring of histidine, yielding 1-methylhistidine (or pi-methylhistidine) or 3-methylhistidine (tau-methylhistidine). While protein histidine methylation in mammals was discovered more than 50 years ago, the first histidine methyltransferases were identified only recently. So far, four different human protein histidine methyltransferases have been uncovered, and one of these is METTL9, which is responsible for introducing 1-methylhistidine in a number of proteins. The minimal sequence motif that is required, though not always sufficient, for METTL9-mediated methylation is His-X-His (HxH), where X is preferentially a small uncharged residue. Many METTL9 substrates are methylated at stretches of alternating histidines, i.e., several adjoining HxH motifs, such as HxHxH. Histidines are frequently involved in binding metal ions, such as zinc. Accordingly, it has been shown for several sequences targeted by METTL9, for example, in the immunomodulatory and antibacterial protein S100A9 and the zinc transporter SLC39A7, that histidine methylation diminishes zinc binding and thereby modulates protein function. In this review, we present a detailed account of METTL9-mediated histidine methylation, regarding its discovery, biochemical mechanism, structural features, and biological significance.