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

• DOI: 10.1038/s41467-018-05646-y
• Publication Date: 2018-08-20T11:02:26Z
• Authors: 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
• Keywords: 0301 basic medicine; 570; 0303 health sciences; Science; Q; 610; Methyltransferases; Article; 03 medical and health sciences; Peptide Elongation Factor 1; 540 Chemistry; 570 Life sciences; biology; Humans; RNA, Messenger; Codon; Protein Processing, Post-Translational; Ribosomes; Protein Binding

AbstractEukaryotic 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.