Novel N-terminal and Lysine Methyltransferases That Target Translation Elongation Factor 1A in Yeast and Human

Eukaryotic elongation factor 1A (eEF1A) is an essential, highly methylated protein that facilitates translational elongation by delivering aminoacyl-tRNAs to ribosomes. Here, we report a new eukaryotic protein N-terminal methyltransferase, Saccharomyces cerevisiae YLR285W, which methylates eEF1A at a previously undescribed high-stoichiometry N-terminal site and the adjacent lysine. Deletion of YLR285W resulted in the loss of N-terminal and lysine methylation in vivo, whereas overexpression of YLR285W resulted in an increase of methylation at these sites. This was confirmed by in vitro methylation of eEF1A by recombinant YLR285W. Accordingly, we name YLR285W as elongation factor methyltransferase 7 (Efm7). This enzyme is a new type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. We show that the N-terminal methylation of eEF1A is also present in human; this conservation over a large evolutionary distance suggests it to be of functional importance. This study also reports that the trimethylation of Lys79 in eEF1A is conserved from yeast to human. The methyltransferase responsible for Lys79 methylation of human eEF1A is shown to be N6AMT2, previously documented as a putative N(6)-adenine-specific DNA methyltransferase. It is the direct ortholog of the recently described yeast Efm5, and we show that Efm5 and N6AMT2 can methylate eEF1A from either species in vitro. We therefore rename N6AMT2 as eEF1A-KMT1. Including the present work, yeast eEF1A is now documented to be methylated by five different methyltransferases, making it one of the few eukaryotic proteins to be extensively methylated by independent enzymes. This implies more extensive regulation of eEF1A by this posttranslational modification than previously appreciated. Eukaryotic elongation factor 1A (eEF1A) is an essential, highly methylated protein that facilitates translational elongation by delivering aminoacyl-tRNAs to ribosomes. Here, we report a new eukaryotic protein N-terminal methyltransferase, Saccharomyces cerevisiae YLR285W, which methylates eEF1A at a previously undescribed high-stoichiometry N-terminal site and the adjacent lysine. Deletion of YLR285W resulted in the loss of N-terminal and lysine methylation in vivo, whereas overexpression of YLR285W resulted in an increase of methylation at these sites. This was confirmed by in vitro methylation of eEF1A by recombinant YLR285W. Accordingly, we name YLR285W as elongation factor methyltransferase 7 (Efm7). This enzyme is a new type of eukaryotic N-terminal methyltransferase as, unlike the three other known eukaryotic N-terminal methyltransferases, its substrate does not have an N-terminal [A/P/S]-P-K motif. We show that the N-terminal methylation of eEF1A is also present in human; this conservation over a large evolutionary distance suggests it to be of functional importance. This study also reports that the trimethylation of Lys79 in eEF1A is conserved from yeast to human. The methyltransferase responsible for Lys79 methylation of human eEF1A is shown to be N6AMT2, previously documented as a putative N(6)-adenine-specific DNA methyltransferase. It is the direct ortholog of the recently described yeast Efm5, and we show that Efm5 and N6AMT2 can methylate eEF1A from either species in vitro. We therefore rename N6AMT2 as eEF1A-KMT1. Including the present work, yeast eEF1A is now documented to be methylated by five different methyltransferases, making it one of the few eukaryotic proteins to be extensively methylated by independent enzymes. This implies more extensive regulation of eEF1A by this posttranslational modification than previously appreciated. Protein methylation is emerging as one of the most prominent posttranslational modifications in the eukaryotic cell (1.Khoury G.A. Baliban R.C. Floudas C.A. Proteome-wide post-translational modification statistics: Frequency analysis and curation of the Swiss-prot database.Sci. Rep. 2011; 1 (Article number: 90)Crossref PubMed Scopus (593) Google Scholar). Often showing high evolutionary conservation, it is increasingly recognized for its role in modulating protein–protein interactions (2.Erce M.A. Pang C.N. Hart-Smith G. Wilkins M.R. The methylproteome and the intracellular methylation network.Proteomics. 2012; 12: 564-586Crossref PubMed Scopus (70) Google Scholar). Indeed, it has been documented in protein interaction codes (3.Winter D.L. Erce M.A. Wilkins M.R. A web of possibilities: Network-based discovery of protein interaction codes.J. Proteome Res. 2014; 13: 5333-5338Crossref PubMed Scopus (15) Google Scholar), such as those of the histones and p53 (4.Jenuwein T. Allis C.D. Translating the histone code.Science. 2001; 293: 1074-1080Crossref PubMed Scopus (7633) Google Scholar, 5.Gu B. Zhu W.G. Surf the post-translational modification network of p53 regulation.Int. J. Biol. Sci. 2012; 8: 672-684Crossref PubMed Scopus (162) Google Scholar), where it shows interplay with modifications such as acetylation and phosphorylation. Despite this, there remains a paucity of understanding of the enzymes that catalyze protein methylation. Many of the known methyltransferases target histones. However, many other methyltransferases have been discovered recently that act on nonhistone proteins (6.Clarke S.G. Protein methylation at the surface and buried deep: Thinking outside the histone box.Trends Biochem. Sci. 2013; 38: 243-252Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). While protein methylation predominantly occurs on lysine and arginine residues, it is also known to occur on glutamine, asparagine, glutamate, histidine, cysteine, and the N- and C termini of proteins. Although the presence of N-terminal methylation on numerous proteins has been known for decades (7.Stock A. Clarke S. Clarke C. Stock J. N-terminal methylation of proteins: Structure, function and specificity.FEBS Lett. 1987; 220: 8-14Crossref PubMed Scopus (78) Google Scholar), the first enzymes responsible for this methylation have only recently been discovered (8.Tooley C.E. Petkowski J.J. Muratore-Schroeder T.L. Balsbaugh J.L. Shabanowitz J. Sabat M. Minor W. Hunt D.F. Macara I.G. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein.Nature. 2010; 466: 1125-1128Crossref PubMed Scopus (83) Google Scholar, 9.Webb K.J. Lipson R.S. Al-Hadid Q. Whitelegge J.P. Clarke S.G. Identification of protein N-terminal methyltransferases in yeast and humans.Biochemistry. 2010; 49: 5225-5235Crossref PubMed Scopus (69) Google Scholar). The Saccharomyces cerevisiae protein Tae1 and its human ortholog N-terminal methyltransferase 1 (NTMT1) catalyze N-terminal methylation of proteins with an N-terminal [A/P/S]-P-K motif (after methionine removal). Yet there is evidence that these enzymes may recognize a more general N-terminal motif (10.Petkowski J.J. Schaner Tooley C.E. Anderson L.C. Shumilin I.A. Balsbaugh J.L. Shabanowitz J. Hunt D.F. Minor W. Macara I.G. Substrate specificity of mammalian N-terminal alpha-amino methyltransferase NRMT.Biochemistry. 2012; 51: 5942-5950Crossref PubMed Scopus (37) Google Scholar). Human NTMT2 is a monomethyltransferase that methylates the same substrates as NTMT1 and may prime substrate proteins with monomethylation to assist subsequent trimethylation by NTMT1 (11.Petkowski J.J. Bonsignore L.A. Tooley J.G. Wilkey D.W. Merchant M.L. Macara I.G. Schaner Tooley C.E. NRMT2 is an N-terminal that for its J. 2013; PubMed Scopus Google Scholar). The function of N-terminal methylation on proteins has been recently N-terminal methylation of of protein 1 is known to its to and the T. T.L. C.E. Shabanowitz J. Hunt D.F. Macara I.G. N-terminal of RCC1 is for and Biol. PubMed Scopus Google Scholar, Macara I.G. of by a in the of the factor Biol. PubMed Scopus Google Scholar), and N-terminal methylation of DNA protein is for its role in DNA Q. of protein and its function in Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). there is evidence of interplay N-terminal methylation and other posttranslational modifications T. Petkowski J.J. D.L. Macara I.G. Shabanowitz J. Hunt D.F. modification of the of Sci. 2013; PubMed Scopus Google Scholar), lysine and arginine it may be protein interaction codes (3.Winter D.L. Erce M.A. Wilkins M.R. A web of possibilities: Network-based discovery of protein interaction codes.J. Proteome Res. 2014; 13: 5333-5338Crossref PubMed Scopus (15) Google Scholar). N-terminal methylation therefore to be a modification of functional in the Eukaryotic elongation factor 1A and its ortholog is an elongation factor that is in function is in of aminoacyl-tRNAs to the it is also known to have a role in many other such as and Thinking outside the Biol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). A of methyltransferases have been discovered in S. cerevisiae and human that target elongation of these elongation factor methyltransferases act on Efm5, and and R.S. K.J. Clarke S.G. methyltransferases eukaryotic elongation factor 1A in Saccharomyces Biochem. 2010; PubMed Scopus Google Scholar, K.J. S. Clarke S.G. A new type of protein lysine methyltransferase of elongation factor Res. 2014; PubMed Scopus Google Scholar, J. A. Saccharomyces cerevisiae eukaryotic elongation factor 1A (eEF1A) is methylated at by a PubMed Scopus Google Scholar). Human is the ortholog of in that it eEF1A at which is to in yeast T. J. M. the mammalian methyltransferase to be an lysine 2014; PubMed Scopus (69) Google Scholar). eukaryotic elongation factor is also methylated by a of lysine and act on and Wilkins M.R. of proteins in Saccharomyces Identification of methylated and 2012; 12: PubMed Scopus Google Scholar, J.J. Hart-Smith G. Erce M.A. Wilkins M.R. factor methyltransferase eukaryotic lysine Res. 2014; PubMed Scopus Google Scholar, J. A. C. Identification and of a conserved methyltransferase eukaryotic elongation factor Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, K.J. S. Clarke S.G. of elongation factor protein lysine Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). Human is the ortholog of in that it at which is to in yeast J. A. C. Identification and of a conserved methyltransferase eukaryotic elongation factor Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). Here, we report the N-terminal methylation of eEF1A in S. cerevisiae and the of the methyltransferase that this and we the modification to the N-terminal and show it is conserved in the human We also show that YLR285W, which we rename elongation factor methyltransferase 7 is responsible for this modification in as as at the adjacent lysine. We also the methyltransferases responsible for methylation of lysine in Human N6AMT2 is shown to be the ortholog of yeast Efm5 its to methylate yeast and human eEF1A at Lys79 in vitro. We therefore rename N6AMT2 as eEF1A-KMT1. The yeast in this study was and from and to J.J. Hart-Smith G. Erce M.A. Wilkins M.R. factor methyltransferase eukaryotic lysine Res. 2014; PubMed Scopus Google Scholar). The was for overexpression of YLR285W by J. for highly of than PubMed Scopus Google to the and the YLR285W with the and a was on this to the YLR285W only the and the to the in was as J. M. of protein substrates by protein PubMed Scopus Google Scholar), that the was by on with and with with and with with T. for protein and 12: PubMed Scopus Google and to with and to a of at and from the with for and for in a for in by and by previously described G. and of and 2012; PubMed Scopus Google analysis on either an a for on the in the at with an target of 1 in the The was to in in with an the of the for the methylation of The five most of on the and by to the five most not of on the with an of of and at a target of for analysis in the was with an of on the target in the at The was to in in with an the of the for the methylation of The most of on the and the and target 1 in the was as for most and of not of on the only have been than have been was for most with an of to either from the and M. for PubMed Scopus Google Scholar). the to by the and for with the the and to N-terminal methylation the was to and the modifications and of with and and and different methylation to the the methylated that to of which by for of to only with for by of of the and a to only have been to the A. T. M. G. A. J.P. S. and 2014; PubMed Scopus Google the with the analysis of the of by on a the the of methylation of the N-terminal to was to of at these the The for the target from the methylated to of for with the in the Human eEF1A in the same that the only the of the N-terminal and for at analysis of on an the with the The was to A as its the the was to the of methylation of the to by of of for of yeast in and methionine yeast with methionine as protein and by and the to eEF1A by and by as for by with the to a at the for yeast and human N6AMT2 and at the C for other from yeast and cerevisiae eukaryotic elongation factor eukaryotic elongation factor by in cell yeast and from DNA with and for and recombinant proteins and to J.J. Hart-Smith G. Erce M.A. Wilkins M.R. factor methyltransferase eukaryotic lysine Res. 2014; PubMed Scopus Google Scholar). Saccharomyces cerevisiae eukaryotic elongation factor 1A eukaryotic elongation factor 1A lysine methyltransferase by in cell from with methyltransferase N6AMT2, at in the presence of in in vitro methylation 1 at for and and a of to a of 1 for the enzyme was for the was to which by and for as over yeast eEF1A has been known to have different of methylation J. W. of yeast of post-translational PubMed Scopus Google Scholar). It was therefore to of and from the of eEF1A the three five the we eEF1A This the N-terminal the N-terminal is and the adjacent lysine to five in this for of methylation three of the five to and the to confirmed that this methylation is the of methylation we the to the of its N-terminal and that the and of the only of and the and of the only and of and and not in this that the of eEF1A is at is and on to the and that the N-terminal and of eEF1A we to the eEF1A from of the putative protein methyltransferases YLR285W, and T. J. M. A. A. M. to substrate specificity of Biol. 2014; PubMed Scopus Google only a loss of N-terminal and methylation in of eEF1A from and confirmed this, showing a loss of N-terminal and methylation This also that the N-terminal present in the and of the was of high to be We the overexpression of YLR285W in yeast to a of methylation on the N-terminal YLR285W overexpression methylation at sites. was as with the N-terminal trimethylation increase in the was also with a of and trimethylation This is with trimethylation of the and of for of from YLR285W, also the presence of of not these that YLR285W is the enzyme responsible for N-terminal and a we YLR285W methylate eEF1A in vitro. YLR285W was with recombinant yeast eEF1A from in the presence of This resulted in the of and of eEF1A on the N-terminal which that the of eEF1A may be its to be methylated by YLR285W in vitro. on and in vitro methylation we that YLR285W is an N-terminal and lysine methyltransferase that can methylate the N-terminal and of with the of methyltransferases that act on elongation we YLR285W be elongation factor methyltransferase 7 (Efm7). The human N-terminal methyltransferase NTMT1 an N-terminal motif and can methylate (8.Tooley C.E. Petkowski J.J. Muratore-Schroeder T.L. Balsbaugh J.L. Shabanowitz J. Sabat M. Minor W. Hunt D.F. Macara I.G. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein.Nature. 2010; 466: 1125-1128Crossref PubMed Scopus (83) Google Scholar). we that was to methylate a to the N-terminal of eEF1A not of this and the in vitro we therefore of eEF1A methylation. eEF1A and it to as its of and the of these in the We therefore the of a of the of to methylate recombinant eEF1A in vitro. of either the was to the of resulted in the of of trimethylation that the of eEF1A is for and methylation by and that may with eEF1A at from the site of methylation. We to which of eEF1A for this We the of to methylate 1 of eEF1A in 1 and this to the methylation of eEF1A 1 vitro methylation of recombinant of these proteins that is of 1 and 1 1 and 1 more than with 1 also to a This that 1 is for methylation by the presence of the other can the these that the of eEF1A the of to methylate that only 1 is for methylation to the high of conservation of many other N-terminal methylation (8.Tooley C.E. Petkowski J.J. Muratore-Schroeder T.L. Balsbaugh J.L. Shabanowitz J. Sabat M. Minor W. Hunt D.F. Macara I.G. NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein.Nature. 2010; 466: 1125-1128Crossref PubMed Scopus (83) Google Scholar), we the N-terminal methylation of eEF1A in yeast is conserved in human an of proteins from we an N-terminal of from trimethylation on with the yeast there was a analysis of the confirmed that it only of and that therefore the trimethylation of the and is N-terminal analysis of an of confirmed the of the we not the of the that is in It was not to the human of eEF1A and as in for the first However, this conservation of the N-terminal of eEF1A it that human N-terminal trimethylation of eEF1A is therefore a highly conserved modification yeast and human. we as the methyltransferase responsible for the N-terminal methylation of yeast eEF1A and that human eEF1A is also we to methylate human eEF1A in vitro. of with in the presence of not in N-terminal methylation was to methylate in vitro the same This suggests N-terminal methylation is conserved yeast and the methyltransferases that catalyze the have and that the eEF1A from one species can only be methylated by its methyltransferase. It is not protein is to be the methyltransferase responsible for N-terminal methylation of eEF1A in human. The human protein to is of However, we that the is not as the yeast protein to is of 7 is the yeast protein to human of a report loss of eEF1A trimethylation at Lys79 of This enzyme was Efm5 K.J. S. Clarke S.G. A new type of protein lysine methyltransferase of elongation factor Res. 2014; PubMed Scopus Google Scholar). We to this the recently described This to lysine and arginine the of methylated and to be as it at and T. for protein and 12: PubMed Scopus Google Scholar). we a loss of and trimethylation of Lys79 of of human eEF1A has been as in A. J. M. J. J. and analysis of protein 2014; 13: Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. M. T. and of lysine and arginine methylation in the human 2013; PubMed Scopus Google Scholar, of protein lysine methylation in 2013; 8: PubMed Scopus Google Scholar). We confirmed this with analysis of proteins this methylation site is conserved yeast and we for the human ortholog of A of Efm5 human proteins in N6AMT2 N(6)-adenine-specific DNA as the with an of the Efm5 as the with an of 7 The of Efm5 and N6AMT2 high and the presence of the and N6AMT2 also a which is of methylation K.J. S. Clarke S.G. A new type of protein lysine methyltransferase of elongation factor Res. 2014; PubMed Scopus Google Scholar). We therefore N6AMT2 methylate human yeast eEF1A in vitro. we to Efm5 methyltransferase in as this has not been of Efm5 N6AMT2 with recombinant yeast eEF1A recombinant human of eEF1A in resulted in a of methylation at of the from and of shown in and Efm5 and N6AMT2 can methylate yeast and human eEF1A in vitro. This that trimethylation of Lys79 in eEF1A and the methyltransferases that catalyze it highly conserved in Efm5 to methylate more than and N6AMT2 to methylate more than This conservation, there may be the enzymes substrates that methylation to more with enzymes substrates from the same This may be to in such as the yeast and human of the methylated Lys79 in in three with J. A. C. Identification and of a conserved methyltransferase eukaryotic elongation factor Biol. 2014; Full Text Full Text PDF PubMed Scopus Google and there to be numerous methyltransferases of eEF1A in we N6AMT2 be eEF1A-KMT1. Here, we have shown that the new yeast enzyme which was previously to be a K.J. J.G. and by in Saccharomyces PubMed Scopus Google Scholar), is in a protein N-terminal and lysine methyltransferase of It a new type of N-terminal methyltransferase as it to the of methyltransferases unlike the three other known eukaryotic N-terminal methyltransferases that to a of proteins to be N-terminal methyltransferases methyltransferases have to be lysine Wilkins M.R. of proteins in Saccharomyces Identification of methylated and 2012; 12: PubMed Scopus Google Scholar, J. A. C. Identification and of a conserved methyltransferase eukaryotic elongation factor Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. A. S. W. methylation of by a of a human protein methyltransferase 2012; PubMed Scopus Google Scholar, M. M. B. A of lysine methyltransferases with to 2013; PubMed Scopus Google Scholar, A. W. S. Identification and of a human methyltransferase modulating protein function lysine Biol. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, R.C. methyltransferase is an conserved enzyme that in 2010; PubMed Scopus Google Scholar). therefore also the first methyltransferase that is not lysine It is not that is the methyltransferase responsible for N-terminal and methylation of yeast This is there is high the N-terminal and the lysine the of the N-terminal is the the of the lysine is a substrate that is only methylated the is the first methyltransferase that can methylate at the of a protein as as adjacent It is that eEF1A is the only substrate of in vitro methylation of yeast with methylation of a which to the of eEF1A T. J. J. A. M. A. and substrate specificity of the Saccharomyces cerevisiae 2011; PubMed Scopus Google Scholar). However, that eEF1A is one of the most proteins in the it is that substrates may have in vitro may not have been to methylation of It therefore remains that has other there other yeast proteins with an N-terminal and a of the However, as for and methylation of its it be to these has only one this be with that for a of other methyltransferases J. A. C. Identification and of a conserved methyltransferase eukaryotic elongation factor Biol. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar, S. M. A. S. W. methylation of by a of a human protein methyltransferase 2012; PubMed Scopus Google Scholar, A. W. S. Identification and of a human methyltransferase modulating protein function lysine Biol. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). While it is for the cell to a methyltransferase to a a increase for protein by the modification of eEF1A this and an evolutionary has been to have at the with type K.J. J.G. and by in Saccharomyces PubMed Scopus Google Scholar). This was to be to its putative function as a However, in of its protein methyltransferase it that this is to the loss of methylation on eEF1A it be to loss of methylation on as substrate of the N-terminal methylation by is in 1 of which is its However, the site is not the is to the of it is to the of trimethylation a on the of the it has been this may to the of (7.Stock A. Clarke S. Clarke C. Stock J. N-terminal methylation of proteins: Structure, function and specificity.FEBS Lett. 1987; 220: 8-14Crossref PubMed Scopus (78) Google Scholar). Indeed, it has been shown that N-terminal methylation can the interaction of proteins with DNA C. Q. Identification of of that its to the Proteome Res. 2013; 12: PubMed Scopus Google Scholar). The trimethylation may therefore the of it may the protein–protein interactions of eEF1A in a to that of lysine and arginine methylation of proteins (2.Erce M.A. Pang C.N. Hart-Smith G. Wilkins M.R. The methylproteome and the intracellular methylation network.Proteomics. 2012; 12: 564-586Crossref PubMed Scopus (70) Google Scholar, M.A. Hart-Smith G. Wilkins M.R. by arginine methylation in the yeast interaction 2013; 12: Full Text Full Text PDF PubMed Scopus Google Scholar, D.L. Hart-Smith G. Erce M.A. Wilkins M.R. methylation the interactions of yeast C PubMed Scopus Google Scholar). the conservation of this modification yeast and it be of to the functional role of eEF1A N-terminal methylation in more The human protein to is However, the the recently described which methylates eEF1A at J. A. Saccharomyces cerevisiae eukaryotic elongation factor 1A (eEF1A) is methylated at by a PubMed Scopus Google Scholar). It is therefore is the ortholog of and therefore the human eEF1A N-terminal methyltransferase. it may be that human methyltransferase of known substrate is the ortholog of such as also of the of This study also reports N6AMT2 as the human ortholog of shown to act as lysine methyltransferases to eEF1A Lys79 in of the loss of methylation on of K.J. S. Clarke S.G. A new type of protein lysine methyltransferase of elongation factor Res. 2014; PubMed Scopus Google Scholar). Efm5 is and in S. A. analysis of protein in PubMed Scopus Google Scholar). is in most at to high and is also predominantly M. C. A. C. A. S. C.A. J. S. T. J. J. M. M. M. G. J. of the human PubMed Scopus Google Scholar, C. M. M. M. A. M. the protein in three human cell Proteome Res. 2011; PubMed Scopus Google Scholar). This that of is in many M. C. C.A. B. A. C. M. A. C. J. M. A. C. M. M. G. C. M. W. J. J. J. J. A. J. M. A. A. J. M. S. M. S. A. J. J. S. A human protein for and on Full Text Full Text PDF PubMed Scopus Google Scholar), which may a translational function of the methylation of Lys79 in eEF1A to the protein of and Efm5 to be N(6)-adenine-specific DNA is of of N(6)-adenine-specific DNA the human protein was to be a protein methyltransferase to of factor 1 S. on human methylates factor Lett. PubMed Scopus Google Scholar). The in with the that methyltransferases lysine the in methyltransferase substrate specificity on it was recently that a which is present in Efm5, and may be a general motif for the and methylation of K.J. S. Clarke S.G. A new type of protein lysine methyltransferase of elongation factor Res. 2014; PubMed Scopus Google Scholar). This is to the motif of methyltransferases S. M. A. S. W. methylation of by a of a human protein methyltransferase 2012; PubMed Scopus Google and suggests that a general motif may be with methylation. now a of five known methyltransferases that target eEF1A in yeast While the function of methylation is the that act one protein suggests may of eEF1A Thinking outside the Biol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). The in of the methylation which from for the N-terminal methylation to and for other G. Wilkins M.R. of Saccharomyces cerevisiae lysine protein lysine methyltransferase Proteome Res. 2014; 13: PubMed Scopus Google Scholar), is also of However, the for the N-terminal methylation be confirmed by a more such as to a direct with G. Wilkins M.R. of Saccharomyces cerevisiae lysine protein lysine methyltransferase Proteome Res. 2014; 13: PubMed Scopus Google Scholar). It is that methylation can as protein analysis that eEF1A at an to is for lysine methylation N-terminal acetylation R.S. K.J. Clarke S.G. methyltransferases eukaryotic elongation factor 1A in Saccharomyces Biochem. 2010; PubMed Scopus Google Scholar), now known to be N-terminal the function of methylation the of methyltransferase be with yeast for a of different that eEF1A is known to be such as protein and Thinking outside the Biol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). It is to that there few other proteins known to be methylated by many such is the protein which is methylated at by five different methyltransferases of p53 function by lysine 2011; PubMed Scopus Google Scholar). of these is known to have different in modulating the of p53 of p53 function by lysine 2011; PubMed Scopus Google Scholar). is histone which is methylated at by many different methyltransferases, of which have in modulating a in and 2012; 13: PubMed Scopus Google Scholar). It is therefore that the eEF1A methyltransferases have in modulating the of This may be by eEF1A by which it in by modulating its that lysine methylation is known to protein–protein interactions D.L. Hart-Smith G. Erce M.A. Wilkins M.R. methylation the interactions of yeast C PubMed Scopus Google Scholar). at the the of the of cell was a from and with

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