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

• Published in: Nature communications Vol. 9; no. 1; pp. 3411 - 15
• Main Authors: Jakobsson, Magnus E., Małecki, Jędrzej M., Halabelian, Levon, Nilges, Benedikt S., Pinto, Rita, Kudithipudi, Srikanth, Munk, Stephanie, Davydova, Erna, Zuhairi, Fawzi R., Arrowsmith, Cheryl H., Jeltsch, Albert, Leidel, Sebastian A., Olsen, Jesper V., Falnes, Pål Ø.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.08.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 38; 38/91; 631/1647/2067; 631/45/173; 631/45/612/1238; 631/535/1266; 82/58; Biochemistry; Codon - genetics; Codons; E coli; Elongation; Enzymes; Experiments; Humanities and Social Sciences; Humans; Mass spectrometry; Methylation; Methyltransferase; Methyltransferases - chemistry; Methyltransferases - genetics; Methyltransferases - metabolism; mRNA; multidisciplinary; Peptide Elongation Factor 1 - chemistry; Peptide Elongation Factor 1 - genetics; Peptide Elongation Factor 1 - metabolism; Peptides; Post-translation; Protein Binding; Protein biosynthesis; Protein Processing, Post-Translational; Protein synthesis; Proteins; Proteomics; Ribosomes - metabolism; RNA, Messenger - metabolism; Science; Science (multidisciplinary); Scientific imaging; Translation; Translation elongation; tRNA
• DOI: 10.1038/s41467-018-05646-y
• ISSN: 2041-1723

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. Eukaryotic elongation factor 1 alpha (eEF1A) is subject to extensive post-translational methylation but not all responsible enzymes are known. Here, the authors identify METTL13 as an eEF1A methyltransferase with dual specificity, which is involved in the codon-specific modulation of mRNA translation.