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

Davydova, Erna ; Shimazu, Tadahiro ; Schuhmacher, Maren Kirstin ; Jakobsson, Magnus E. LU ; Willemen, Hanneke L.D.M. ; Liu, Tongri ; Moen, Anders ; Ho, Angela Y.Y. ; Małecki, Jędrzej and Schroer, Lisa , et al. (2021) In Nature Communications 12(1).
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
12
issue
1
article number
891
publisher
Nature Publishing Group
external identifiers
  • scopus:85100703102
  • pmid:33563959
ISSN
2041-1723
DOI
10.1038/s41467-020-20670-7
language
English
LU publication?
yes
id
419e306e-49a8-4c67-8467-3a7fe7708458
date added to LUP
2021-03-01 07:57:32
date last changed
2024-04-18 02:39:13
@article{419e306e-49a8-4c67-8467-3a7fe7708458,
  abstract     = {{<p>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.</p>}},
  author       = {{Davydova, Erna and Shimazu, Tadahiro and Schuhmacher, Maren Kirstin and Jakobsson, Magnus E. and Willemen, Hanneke L.D.M. and Liu, Tongri and Moen, Anders and Ho, Angela Y.Y. and Małecki, Jędrzej and Schroer, Lisa and Pinto, Rita and Suzuki, Takehiro and Grønsberg, Ida A. and Sohtome, Yoshihiro and Akakabe, Mai and Weirich, Sara and Kikuchi, Masaki and Olsen, Jesper V. and Dohmae, Naoshi and Umehara, Takashi and Sodeoka, Mikiko and Siino, Valentina and McDonough, Michael A. and Eijkelkamp, Niels and Schofield, Christopher J. and Jeltsch, Albert and Shinkai, Yoichi and Falnes, Pål}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes}},
  url          = {{http://dx.doi.org/10.1038/s41467-020-20670-7}},
  doi          = {{10.1038/s41467-020-20670-7}},
  volume       = {{12}},
  year         = {{2021}},
}