The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates

Magnus E. Jakobsson; Jędrzej M Małecki; Levon Halabelian; Benedikt S Nilges; Rita Pinto; Srikanth Kudithipudi; Stephanie Munk; Erna Davydova; Fawzi R Zuhairi; Cheryl H Arrowsmith; Albert Jeltsch; Sebastian A Leidel; Jesper V. Olsen; Pål Ø Falnes

doi:10.1038/s41467-018-05646-y

The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates

Magnus E. Jakobsson, Jędrzej M Małecki, Levon Halabelian, Benedikt S Nilges, Rita Pinto, Srikanth Kudithipudi, Stephanie Munk, Erna Davydova, Fawzi R Zuhairi, Cheryl H Arrowsmith, Albert Jeltsch, Sebastian A Leidel, Jesper V. Olsen, Pål Ø Falnes

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Abstract

Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is subject to extensive post-translational methylation, but several of the responsible enzymes remain unknown. Using a wide range of experimental approaches, we here show that human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively. Our biochemical and structural analyses provide detailed mechanistic insights into recognition of the eEF1A N terminus by METTL13. Moreover, through ribosome profiling, we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rates of specific codons. In summary, we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner.

Original language	English
Article number	3411
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-05646-y
Publication status	Published - 1 Dec 2018

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The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation ratesFinal published version, 1.8 MB

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Jakobsson, M. E., Małecki, J. M., Halabelian, L., Nilges, B. S., Pinto, R., Kudithipudi, S., Munk, S., Davydova, E., Zuhairi, F. R., Arrowsmith, C. H., Jeltsch, A., Leidel, S. A., Olsen, J. V., & Falnes, P. Ø. (2018). The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates. Nature Communications, 9(1), [3411]. https://doi.org/10.1038/s41467-018-05646-y

Jakobsson, ME, Małecki, JM, Halabelian, L, Nilges, BS, Pinto, R, Kudithipudi, S, Munk, S, Davydova, E, Zuhairi, FR, Arrowsmith, CH, Jeltsch, A, Leidel, SA, Olsen, JV & Falnes, PØ 2018, 'The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates', Nature Communications, vol. 9, no. 1, 3411. https://doi.org/10.1038/s41467-018-05646-y

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title = "The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates",

abstract = "Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is subject to extensive post-translational methylation, but several of the responsible enzymes remain unknown. Using a wide range of experimental approaches, we here show that human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively. Our biochemical and structural analyses provide detailed mechanistic insights into recognition of the eEF1A N terminus by METTL13. Moreover, through ribosome profiling, we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rates of specific codons. In summary, we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner.",

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T1 - The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates

AU - Jakobsson, Magnus E.

AU - Małecki, Jędrzej M

AU - Halabelian, Levon

AU - Nilges, Benedikt S

AU - Pinto, Rita

AU - Kudithipudi, Srikanth

AU - Munk, Stephanie

AU - Davydova, Erna

AU - Zuhairi, Fawzi R

AU - Arrowsmith, Cheryl H

AU - Jeltsch, Albert

AU - Leidel, Sebastian A

AU - Olsen, Jesper V.

AU - Falnes, Pål Ø

PY - 2018/12/1

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N2 - Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is subject to extensive post-translational methylation, but several of the responsible enzymes remain unknown. Using a wide range of experimental approaches, we here show that human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively. Our biochemical and structural analyses provide detailed mechanistic insights into recognition of the eEF1A N terminus by METTL13. Moreover, through ribosome profiling, we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rates of specific codons. In summary, we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner.

AB - Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is subject to extensive post-translational methylation, but several of the responsible enzymes remain unknown. Using a wide range of experimental approaches, we here show that human methyltransferase (MTase)-like protein 13 (METTL13) contains two distinct MTase domains targeting the N terminus and Lys55 of eEF1A, respectively. Our biochemical and structural analyses provide detailed mechanistic insights into recognition of the eEF1A N terminus by METTL13. Moreover, through ribosome profiling, we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rates of specific codons. In summary, we here unravel the function of a human MTase, showing that it methylates eEF1A and modulates mRNA translation in a codon-specific manner.

U2 - 10.1038/s41467-018-05646-y

DO - 10.1038/s41467-018-05646-y

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C2 - 30143613

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3411

ER -

The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates

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