A new type of protein lysine methyltransferase trimethylates Lys-79 of elongation factor 1A

Dzialo, Maria C.; Travaglini, Kyle J.; Shen, Sean; Loo, Joseph A.; Clarke, Steven

doi:10.1016/j.bbrc.2014.11.022

Cited by 18 publications

(18 citation statements)

References 32 publications

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“…We propose N6AMT2 be renamed eEF1A-KMT1. specific to eEF1A Lys 79 in vitro, extending previous observations of the loss of methylation on knockout of EFM5 (18). In yeast, Efm5 is cytosolic and exists in medium abundance (45).…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Aresupporting

confidence: 70%

“…This enzyme was then renamed Efm5 (18). We were able to confirm this result utilizing the recently described LysargiNase Archaea protease.…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Aresupporting

confidence: 60%

“…5). N6AMT2 also showed a [D/N]XX[Y/F] motif, which is suggestive of nitrogen methylation activity (18). We therefore investigated whether N6AMT2 could methylate human and/or yeast eEF1A in vitro.…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Arementioning

confidence: 99%

“…The above errors in classification, along with our disproving the notion that Family 16 methyltransferases are lysine specific, demonstrate the difficulty in assigning methyltransferase substrate specificity based on sequence alone. Nevertheless, it was recently proposed that a (D/N)XX(Y/F) motif, which is present in Efm5, eEF1A-KMT1, and Efm7, may be a general motif for the recognition and methylation of nitrogen atoms (18). This is similar to the (D/E)XX(Y/F) motif characteristic of Family 16 methyltransferases (37) and suggests that a general (D/E/N)XX(Y/F) motif may be associated with nitrogen methylation.…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Arementioning

confidence: 99%

“…A number of methyltransferases have been discovered in both S. cerevisiae and human that target translation elongation factors. In yeast, four of these elongation factor methyltransferases (EFMs) act on eEF1A, namely Efm1, Efm4, Efm5, and Efm6, generating monomethylated Lys 30 , dimethylated Lys 316 , trimethylated Lys 79 , and monomethylated Lys 390 , respectively (17)(18)(19). Human METTL10 is the ortholog of Efm4 in that it trimethylates eEF1A at Lys 318 , which is equivalent to Lys 316 in yeast (20).…”

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confidence: 99%

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

Hamey

Winter

Yagoub

et al. 2016

Molecular & Cellular Proteomics

102

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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 Lys 79 in eEF1A is conserved from yeast to human. The methyltransferase responsible for Lys 79 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. Molecular & Cellular Proteomics

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Section: Methyltransferases That Act On Lysine 79 In Eef1a Aresupporting

confidence: 70%

“…This enzyme was then renamed Efm5 (18). We were able to confirm this result utilizing the recently described LysargiNase Archaea protease.…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Aresupporting

confidence: 60%

Section: Methyltransferases That Act On Lysine 79 In Eef1a Arementioning

confidence: 99%

Section: Methyltransferases That Act On Lysine 79 In Eef1a Arementioning

confidence: 99%

mentioning

confidence: 99%