Comprehensive Structural and Substrate Specificity Classification of the Saccharomyces cerevisiae Methyltransferome

Włodarski, Tomasz; Kutner, Jan; Towpik, Joanna; Kniżewski, Łukasz; Rychlewski, Leszek; Kudlicki, Andrzej; Rowicka, Maga; Dziembowski, Andrzej; Ginalski, Krzysztof

doi:10.1371/journal.pone.0023168

Cited by 52 publications

(85 citation statements)

References 63 publications

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“…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%

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%

Translational Roles of Elongation Factor 2 Protein Lysine Methylation

Dzialo¹,

Travaglini²,

Shen³

et al. 2014

Journal of Biological Chemistry

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“…Previous in vitro methylation of yeast lysate with YLR285W/ Efm7 showed methylation of a single ϳ50kDa band, which corresponds to the mass of eEF1A (41). However, given that eEF1A is one of the most abundant proteins in the cell, it is possible that other, much less abundant substrates may have gone undetected.…”

Section: Methyltransferases That Act On Lysine 79 In Eef1a Arementioning

confidence: 97%

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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“…These proteins, and the enzymes that modify them, have been extensively studied from the intersection of two research directions. In the first place, the combination of bioinformatics and the biology of Saccharomyces cerevisiae have allowed an approach to identify methylated sites in yeast proteins (23,24,29,30). Bioinformatic analyses have allowed for the identification of open reading frames for candidate methyltransferases from genomic DNA sequences both of the major seven beta-strand family and of the SET domain, SPOUT, and other structural families (31-35).…”

Section: Yeast Ribosomes and The Discovery Of Novel Methyltransferasesmentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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Comprehensive Structural and Substrate Specificity Classification of the Saccharomyces cerevisiae Methyltransferome

Cited by 52 publications

References 63 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

The ribosome: A hot spot for the identification of new types of protein methyltransferases

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