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.
Highlights
Eukaryotic elongation factor 1 alpha delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis
During our recent efforts to characterize methylation events on Eukaryotic elongation factor 1 alpha (eEF1A), we noticed that its N terminus is trimethylated in cultured human cells, and this was recently observed and published by others[14]
We report the identification of human methyltransferase (MTase)-like protein 13 (METTL13) as a dual MTase that targets both the N terminus and Lys[55] of eEF1A through two distinct MTase domains, firmly establishing its function using a combination of in vitro and in vivo methods
Summary
Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Despite being first described more than three decades ago, N-terminal methylation represents a poorly characterized PTM and, to date, only two human N-terminal methyltransferases—NTMT1 and NTMT2—have been identified[8,9] Both the NTMT enzymes recognize and target a X-Pro-Lys consensus sequence and several substrates including the regulator of chromosome condensation (RCC1) and the histone H3-like centromeric protein A (CENP-A) have been identified. Both for RCC1 and CENP-A, the lack of N-terminal methylation was shown to cause defects related to the formation and function of the mitotic spindle[10,11]. Human KMTs targeting Lys3615, Lys7914, Lys16516,17, and Lys31818 have recently been identified, but the enzyme(s) targeting Lys[55] and the N terminus have so far remained elusive
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