The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes

Post-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes. METTL9-catalyzed methylation requires a His-x-His (HxH) motif, where x is preferably a small amino acid, allowing METTL9 to methylate a number of HxH-containing proteins, including the immunomodulatory protein S100A9 and the NDUFB3 subunit of mitochondrial respiratory Complex I. Notably, METTL9-mediated methylation enhances respiration via Complex I, and the presence of 1MH in an HxH-containing peptide reduced its zinc binding affinity. Our results establish METTL9-mediated 1MH as a pervasive protein modification, thus setting the stage for further functional studies on protein histidine methylation. Only very few enzymes are known to catalyze protein histidine methylation. Here, the authors show that METTL9 is responsible for most 1-methylhistidine modifications in mouse and human proteomes, and characterize METTL9 ' s substrate specificity and potential cellular functions.

Automated summary

Post-translational methylation, specifically protein histidine methylation, is crucial for optimizing protein function. METTL9 is identified as a broad-specificity methyltransferase responsible for the majority of 1-methylhistidine modifications in mouse and human proteomes. The methylation catalyzed by METTL9 enhances respiration via Complex I, and reduces the zinc binding affinity of HxH-containing peptides.