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 () and Pål Ø. Falnes ()
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Magnus E. Jakobsson: University of Oslo
Jędrzej M. Małecki: University of Oslo
Levon Halabelian: University of Toronto
Benedikt S. Nilges: Max Planck Institute for Molecular Biomedicine
Rita Pinto: University of Oslo
Srikanth Kudithipudi: Stuttgart University
Stephanie Munk: University of Copenhagen
Erna Davydova: University of Oslo
Fawzi R. Zuhairi: University of Oslo
Cheryl H. Arrowsmith: University of Toronto
Albert Jeltsch: Stuttgart University
Sebastian A. Leidel: Max Planck Institute for Molecular Biomedicine
Jesper V. Olsen: University of Copenhagen
Pål Ø. Falnes: University of Oslo

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05646-y

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