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.

Erna Davydova ^# ¹, Tadahiro Shimazu ^# ², Maren Kirstin Schuhmacher ³, Magnus E Jakobsson ⁴ ⁵, Hanneke L D M Willemen ⁶, Tongri Liu ⁷, Anders Moen ¹, Angela Y Y Ho ¹, Jędrzej Małecki ¹, Lisa Schroer ¹, Rita Pinto ¹ ⁸, Takehiro Suzuki ⁹, Ida A Grønsberg ¹, Yoshihiro Sohtome ¹⁰ ¹¹, Mai Akakabe ¹⁰, Sara Weirich ³, Masaki Kikuchi ¹², Jesper V Olsen ⁴, Naoshi Dohmae ⁹, Takashi Umehara ¹², Mikiko Sodeoka ¹⁰ ¹¹, Valentina Siino ⁵, Michael A McDonough ⁷, Niels Eijkelkamp ⁶, Christopher J Schofield ⁷, Albert Jeltsch ¹³, Yoichi Shinkai ¹⁴, Pål Ø Falnes ¹⁵

Affiliations

1 Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316, Oslo, Norway.
2 Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
3 Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
4 Proteomics Program, Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Protein Research (NNF-CPR), University of Copenhagen, Blegdamsvej 3B, 2200, Copenhagen, Denmark.
5 Department of Immunotechnology, Lund University, Medicon Village, 22100, Lund, Sweden.
6 Center for Translational Immunology (CTI), University Medical Center Utrecht, Utrecht University, 3584, Utrecht, EA, The Netherlands.
7 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.
8 Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
9 Biomolecular Characterization Unit, Technology Platform Division, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
10 Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
11 RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
12 Laboratory for Epigenetics Drug Discovery, RIKEN Center for Biosystems Dynamics Research, Yokohama, Japan.
13 Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany. albert.jeltsch@ibtb.uni-stuttgart.de.
14 Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan. yshinkai@riken.jp.
15 Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, 0316, Oslo, Norway. pal.falnes@ibv.uio.no.
# Contributed equally.

PMID: 33563959 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.

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