TY - JOUR
T1 - The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes
AU - Davydova, Erna
AU - Shimazu, Tadahiro
AU - Schuhmacher, Maren Kirstin
AU - Jakobsson, Magnus E
AU - Willemen, Hanneke L D M
AU - Liu, Tongri
AU - Moen, Anders
AU - Ho, Angela Y Y
AU - Małecki, Jędrzej
AU - Schroer, Lisa
AU - Pinto, Rita
AU - Suzuki, Takehiro
AU - Grønsberg, Ida A
AU - Sohtome, Yoshihiro
AU - Akakabe, Mai
AU - Weirich, Sara
AU - Kikuchi, Masaki
AU - Olsen, Jesper V
AU - Dohmae, Naoshi
AU - Umehara, Takashi
AU - Sodeoka, Mikiko
AU - Siino, Valentina
AU - McDonough, Michael A
AU - Eijkelkamp, Niels
AU - Schofield, Christopher J
AU - Jeltsch, Albert
AU - Shinkai, Yoichi
AU - Falnes, Pål Ø
N1 - Funding Information:
The authors thank Bernd Thiede and Per Magne Ueland for useful discussions. We thank M. Shirouzu for help with recombinant protein production and M. Ledsaak, C. Andreassen, and I.F. Kjønstad for help in construct preparation. We thank the staff of Research Resources Division, RIKEN Center for Brain Science, for generation of Mettl9 KO mice, peptide synthesis, and LC-MS/MS analysis and especially Masaya Usui and Hiromasa Morishita for MRM Quantitation; T. Yamazaki and T. Hirose for providing the hCas9 and dual gRNA plasmid, PX330-B/B, M. Ikeda (RIKEN BDR) for sample preparation and Y. Takeda and Y. Araki for the kind support of mouse neutrophil preparation. We thank Dr. Boudewijn Burgering from University Medical Center Utrecht for the use of Seahorse analyzer instrument. We thank Oslo NorMIC Imaging Platform (Department of Biosciences, University of Oslo) for the use of cell imaging equipment. We thank the Proteoforms@LU proteomics platform at Lund University for instrument support and assistance. This work was supported by the Research Council of Norway (to P.Ø.F.), the Norwegian Cancer Society (to P.Ø.F), the ‘Epigenome Manipulation Project’ of the All-RIKEN Projects (to Y.Sh., M.So., T.S., Y. So. T.U.); the Japan Ministry of Education, Culture, Sports, Science, and Technology Grant-in-Aid for Scientific Research (16K18476) (to T.Sh.); the Lundbeck Foundation [R231-2016-2682 to M. E.J.]; Novo Nordisk Foundation [NNF16OC0022946 to M.E.J., NNF14CC0001 to J.V. O.]; the Crafoord Foundation (to M.E.J.). This work has been supported by the DFG grant JE 252/7-4 (to A.J.). M.A.M and C.J.S. thank the Wellcome Trust and Cancer Research UK for funding.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/2/9
Y1 - 2021/2/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85100703102
U2 - 10.1038/s41467-020-20670-7
DO - 10.1038/s41467-020-20670-7
M3 - Article
C2 - 33563959
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 891
ER -