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

Nat Commun. 2021 Feb 9;12(1):891. doi: 10.1038/s41467-020-20670-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cells, Cultured
  • Histidine / metabolism
  • Humans
  • Mammals / classification
  • Mammals / genetics
  • Mammals / metabolism
  • Methylation
  • Methylhistidines / metabolism*
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mutation
  • Protein Processing, Post-Translational
  • Proteome / chemistry
  • Proteome / metabolism*
  • Substrate Specificity
  • Zinc / metabolism

Substances

  • Methylhistidines
  • Proteome
  • 1-methylhistidine
  • Histidine
  • Methyltransferases
  • Zinc