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

Research output: Contribution to journalArticle


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.


  • Erna Davydova
  • Tadahiro Shimazu
  • Maren Kirstin Schuhmacher
  • Hanneke L.D.M. Willemen
  • Tongri Liu
  • Anders Moen
  • Angela Y.Y. Ho
  • Jędrzej Małecki
  • Lisa Schroer
  • Rita Pinto
  • Takehiro Suzuki
  • Ida A. Grønsberg
  • Yoshihiro Sohtome
  • Mai Akakabe
  • Sara Weirich
  • Masaki Kikuchi
  • Jesper V. Olsen
  • Naoshi Dohmae
  • Takashi Umehara
  • Mikiko Sodeoka
  • Michael A. McDonough
  • Niels Eijkelkamp
  • Christopher J. Schofield
  • Albert Jeltsch
  • Yoichi Shinkai
  • Pål Falnes
External organisations
  • University of Oslo
  • University of Stuttgart
  • University of Copenhagen
  • University Medical Center Utrecht
  • University of Oxford
  • Oslo university hospital
  • RIKEN Cluster for Pioneering Research
  • Utrecht University
  • RIKEN Center for Sustainable Resource Science
  • RIKEN Center for Biosystems Dynamics Research
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
Original languageEnglish
Article number891
JournalNature Communications
Issue number1
Publication statusPublished - 2021
Publication categoryResearch