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

Erna Davydova, Tadahiro Shimazu, Maren Kirstin Schuhmacher, Magnus E. Jakobsson, 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, Valentina Siino, Michael A. McDonough, Niels Eijkelkamp, Christopher J. Schofield, Albert Jeltsch (), Yoichi Shinkai () and Pål Ø. Falnes ()
Additional contact information
Erna Davydova: University of Oslo
Tadahiro Shimazu: Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako
Maren Kirstin Schuhmacher: University of Stuttgart
Magnus E. Jakobsson: University of Copenhagen
Hanneke L. D. M. Willemen: Utrecht University
Tongri Liu: University of Oxford
Anders Moen: University of Oslo
Angela Y. Y. Ho: University of Oslo
Jędrzej Małecki: University of Oslo
Lisa Schroer: University of Oslo
Rita Pinto: University of Oslo
Takehiro Suzuki: Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, Wako
Ida A. Grønsberg: University of Oslo
Yoshihiro Sohtome: Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako
Mai Akakabe: Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako
Sara Weirich: University of Stuttgart
Masaki Kikuchi: Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research
Jesper V. Olsen: University of Copenhagen
Naoshi Dohmae: Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, Wako
Takashi Umehara: Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research
Mikiko Sodeoka: Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako
Valentina Siino: Lund University
Michael A. McDonough: University of Oxford
Niels Eijkelkamp: Utrecht University
Christopher J. Schofield: University of Oxford
Albert Jeltsch: University of Stuttgart
Yoichi Shinkai: Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako
Pål Ø. Falnes: University of Oslo

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20670-7

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