Probabilistic Approach to Predicting Substrate Specificity of Methyltransferases

Szczepińska, Teresa; Kutner, Jan; Kopczyński, Michał; Pawłowski, Krzysztof; Dziembowski, Andrzej; Kudlicki, Andrzej; Ginalski, Krzysztof; Rowicka, Maga

doi:10.1371/journal.pcbi.1003514

Cited by 21 publications

(28 citation statements)

References 30 publications

(48 reference statements)

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“…To fully understand why the elongation factors are methylated, it is essential to uncover these enzymes. Recent work has been done to predict substrate category (protein versus nucleotide versus small molecule) and has correctly predicted Efm3 as a protein methyltransferase (53). However, the specifics of residue type and extent of modification are a much more complex question.…”

Section: Discussionmentioning

confidence: 99%

“…In the budding yeast, S. cerevisiae, 86 known and putative methyltransferases have been identified, with 16 having no known substrates (36,55); of these latter enzymes, six are predicted to have protein substrates (53). Additionally, 40 yeast methyltransferases have human homologs, suggesting that the modifications may be important for a properly functioning cell (56).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Translational Roles of Elongation Factor 2 Protein Lysine Methylation

Dzialo¹,

Travaglini²,

Shen³

et al. 2014

Journal of Biological Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Translational Roles of Elongation Factor 2 Protein Lysine Methylation

Dzialo¹,

Travaglini²,

Shen³

et al. 2014

Journal of Biological Chemistry

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“…Trypsinized eEF1A from knockouts of the putative protein methyltransferases YLR285W, YGR001C, YNL024C, and YNL092W (32) only revealed a loss of N-terminal Gly 2 and Lys 3 methylation in ⌬YLR285W (Supplemental Fig. S3).…”

Section: Ylr285w Is the Methyltransferase Responsible For N-terminal mentioning

confidence: 99%

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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“…Generally, these enzymes fall into three major classes based on their structural folds and binding mechanism of the methyl donor, S -adenosylmethionine (AdoMet): seven-beta-strand (Class I), SET domain, and SPOUT methyltransferases. The majority of SPOUT methyltransferases modify RNA [9,10,11]. The SET domain methyltransferases, such as elongation factor methyltransferase 1 (Efm1), are classical protein lysine modifiers [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

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

Dzialo¹,

Travaglini²,

Shen³

et al. 2014

Biochemical and Biophysical Research Communications

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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.

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Probabilistic Approach to Predicting Substrate Specificity of Methyltransferases

Cited by 21 publications

References 30 publications

Translational Roles of Elongation Factor 2 Protein Lysine Methylation

Translational Roles of Elongation Factor 2 Protein Lysine Methylation

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

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

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