Background: Translational elongation factors are extensively methylated, but the roles of these modifications are not established. Results: Loss of methylation on elongation factor 2 in Saccharomyces cerevisiae by deletion of EFM3/YJR129C or EFM2 results in translational defects. Conclusion: Elongation factor methylation is required for normal translational function. Significance: Protein lysine methylation fine tunes the translational apparatus.

The elongation factors of Saccharomyces cerevisiae are extensively methylated, containing a total of ten methyllysine residues. Elongation factor methyltransferases (Efm1, Efm2, Efm3, and Efm4) catalyze at least four of these modifications. Here we report the identification of a new type of protein lysine methyltransferase, Efm5 (Ygr001c), which was initially classified as N6-adenine DNA methyltransferase-like. Efm5 is required for trimethylation of Lys-79 on EF1A. We directly show the loss of this modification in efm5Δ strains by both mass spectrometry and amino acid analysis. Close homologs of Efm5 are found in vertebrates, invertebrates, and plants, although some fungal species apparently lack this enzyme. This suggests possible unique functions of this modification in S. cerevisiae and higher eukaryotes. The misannotation of Efm5 was due to the presence of a DPPF sequence in post-Motif II, typically associated with DNA methylation. Further analysis of this motif and others like it demonstrates a potential consensus sequence for N-methyltransferases.