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; Pål Falnes

doi:10.1038/s41467-020-20670-7

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 UmeharaMikiko Sodeoka, Valentina Siino, Michael A. McDonough, Niels Eijkelkamp, Christopher J. Schofield, Albert Jeltsch, Yoichi Shinkai, Pål Falnes

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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.

Original language	English
Article number	891
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20670-7
Publication status	Published - 2021

Subject classification (UKÄ)

Biological Sciences

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Davydova, E., Shimazu, T., Schuhmacher, M. K., Jakobsson, M. E., Willemen, H. L. D. M., Liu, T., Moen, A., Ho, A. Y. Y., Małecki, J., Schroer, L., Pinto, R., Suzuki, T., Grønsberg, I. A., Sohtome, Y., Akakabe, M., Weirich, S., Kikuchi, M., Olsen, J. V., Dohmae, N., ... Falnes, P. (2021). The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes. Nature Communications, 12(1), Article 891. https://doi.org/10.1038/s41467-020-20670-7

@article{419e306e49a84c6784673a7fe7708458,

title = "The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes",

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.",

author = "Erna Davydova and Tadahiro Shimazu and Schuhmacher, {Maren Kirstin} and Jakobsson, {Magnus E.} and Willemen, {Hanneke L.D.M.} and Tongri Liu and Anders Moen and Ho, {Angela Y.Y.} and J{\c e}drzej Ma{\l}ecki and Lisa Schroer and Rita Pinto and Takehiro Suzuki and Gr{\o}nsberg, {Ida A.} and Yoshihiro Sohtome and Mai Akakabe and Sara Weirich and Masaki Kikuchi and Olsen, {Jesper V.} and Naoshi Dohmae and Takashi Umehara and Mikiko Sodeoka and Valentina Siino and McDonough, {Michael A.} and Niels Eijkelkamp and Schofield, {Christopher J.} and Albert Jeltsch and Yoichi Shinkai and P{\aa}l Falnes",

year = "2021",

doi = "10.1038/s41467-020-20670-7",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Davydova, E, Shimazu, T, Schuhmacher, MK, Jakobsson, ME, Willemen, HLDM, Liu, T, Moen, A, Ho, AYY, Małecki, J, Schroer, L, Pinto, R, Suzuki, T, Grønsberg, IA, Sohtome, Y, Akakabe, M, Weirich, S, Kikuchi, M, Olsen, JV, Dohmae, N, Umehara, T, Sodeoka, M, Siino, V, McDonough, MA, Eijkelkamp, N, Schofield, CJ, Jeltsch, A, Shinkai, Y & Falnes, P 2021, 'The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes', Nature Communications, vol. 12, no. 1, 891. https://doi.org/10.1038/s41467-020-20670-7

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

PY - 2021

Y1 - 2021

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.

U2 - 10.1038/s41467-020-20670-7

DO - 10.1038/s41467-020-20670-7

M3 - Article

C2 - 33563959

AN - SCOPUS:85100703102

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 891

ER -

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

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