The Protein Histidine Methyltransferase METTL9-From Mechanism to Biological Function.

Area of Science:

• Biochemistry
• Molecular Biology
• Post-translational Modifications

Background:

• Protein histidine methylation, a post-translational modification, occurs at the imidazole ring of histidine residues.
• While discovered over 50 years ago, the enzymes responsible (histidine methyltransferases) were only recently identified.
• Four human histidine methyltransferases are known, including METTL9, which catalyzes 1-methylhistidine formation.

Purpose of the Study:

• To provide a comprehensive review of METTL9-mediated histidine methylation.
• To elucidate the biochemical mechanism, structural features, and biological significance of this modification.
• To highlight the role of METTL9 in modulating protein function through altered metal ion binding.

Main Methods:

• Literature review of studies on protein histidine methylation and METTL9.
• Analysis of sequence motifs (His-X-His) targeted by METTL9.
• Examination of the impact of methylation on zinc binding in proteins like S100A9 and SLC39A7.

Main Results:

• METTL9 preferentially methylates histidine residues within His-X-His motifs, often in alternating histidine stretches.
• Histidine methylation by METTL9 can reduce the affinity of proteins for metal ions like zinc.
• This modulation of metal binding affects the function of various proteins, including S100A9 and SLC39A7.

Conclusions:

• METTL9-mediated histidine methylation is a significant post-translational modification with functional consequences.
• Understanding METTL9's mechanism and substrates is crucial for comprehending cellular processes involving histidine methylation.
• This modification offers a regulatory mechanism for protein function, particularly in metal ion-binding proteins.