Translational Roles of Elongation Factor 2 Protein Lysine Methylation

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

doi:10.1074/jbc.m114.605527

Cited by 19 publications

(38 citation statements)

References 58 publications

(83 reference statements)

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“…enzyme Efm3, encoded by YJR129c and related to human FAM86A, trimethylates eEF2 on Lys509, causing an increase in ribosomal frameshifting and increased sensitivity to antibiotics including sordarin (Davydova et al 2014;Dzialo et al 2014). Efm2 also dimethylates Lys613 (Couttas et al 2012).…”

Section: Aa-trna Delivery By Eef1mentioning

confidence: 99%

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

2016

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In this review, we provide an overview of protein synthesis in the yeast Saccharomyces cerevisiae. The mechanism of protein synthesis is well conserved between yeast and other eukaryotes, and molecular genetic studies in budding yeast have provided critical insights into the fundamental process of translation as well as its regulation. The review focuses on the initiation and elongation phases of protein synthesis with descriptions of the roles of translation initiation and elongation factors that assist the ribosome in binding the messenger RNA (mRNA), selecting the start codon, and synthesizing the polypeptide. We also examine mechanisms of translational control highlighting the mRNA cap-binding proteins and the regulation of GCN4 and CPA1 mRNAs.

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Section: Aa-trna Delivery By Eef1mentioning

confidence: 99%

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

2016

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“…With the realization that ribosomes are major sites of protein methylation, several groups focused on the modifications of the elongation factors that closely interact with the ribosomal protein synthesis machinery (19,67,68). It has been known for many years that lysine residues on elongation factors were modified in both prokaryotes and eukaryotes.…”

Section: Unusual Dual Protein Methyltransferases That May Recognize Bmentioning

confidence: 99%

“…It has been known for many years that lysine residues on elongation factors were modified in both prokaryotes and eukaryotes. In the last few years, seven protein lysine methyltransferases of the SETdomain and seven beta-strand family have been characterized for most of the known modifications for elongation factors 1A, 2, and 3 in yeast and have been designated Efm1 through Efm7 (5,19,67,68). Yeast Efm1, 3, 4, 5, and 6 all appear to be specific for methylating one particular lysine side chain on one specific elongation factor (19,68).…”

Section: Unusual Dual Protein Methyltransferases That May Recognize Bmentioning

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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“…Ribosomal RNA methylation sites are clustered in functional regions of the ribosome, including the peptidyl transferase center and the tRNA binding sites (A/P/E), and have been shown to be important for ribosome assembly, structural stability, and translational accuracy (Piekna-Przybylska et al 2008;Baudin-Baillieu et al 2009). Methylation of tRNAs and elongation and release factors modulates translational accuracy and translation termination efficiency (Johansson and Byström 2005;Polevoda and Sherman 2007;Dzialo et al 2014;Hori 2014). Ribosomal proteins are methylated in the three kingdoms of life, but little is known about the physiological roles of these modifications (Arnold and Reilly 1999;Lee et al 2002;Odintsova et al 2003;Yu et al 2005;Polevoda and Sherman 2007;Nesterchuk et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

Al-Hadid

Roy

Chanfreau

et al. 2016

RNA

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Rpl3, a highly conserved ribosomal protein, is methylated at histidine 243 by the Hpm1 methyltransferase in Saccharomyces cerevisiae. Histidine 243 lies close to the peptidyl transferase center in a functionally important region of Rpl3 designated as the basic thumb that coordinates the decoding, peptidyl transfer, and translocation steps of translation elongation. Hpm1 was recently implicated in ribosome biogenesis and translation. However, the biological role of methylation of its Rpl3 substrate has not been identified. Here we interrogate the role of Rpl3 methylation at H243 by investigating the functional impact of mutating this histidine residue to alanine (rpl3-H243A). Akin to Hpm1-deficient cells, rpl3-H243A cells accumulate 35S and 23S pre-rRNA precursors to a similar extent, confirming an important role for histidine methylation in pre-rRNA processing. In contrast, Hpm1-deficient cells but not rpl3-H243A mutants show perturbed levels of ribosomal subunits. We show that Hpm1 has multiple substrates in different subcellular fractions, suggesting that methylation of proteins other than Rpl3 may be important for controlling ribosomal subunit levels. Finally, translational fidelity assays demonstrate that like Hpm1-deficient cells, rpl3-H243A mutants have defects in translation elongation resulting in decreased translational accuracy. These data suggest that Rpl3 methylation at H243 is playing a significant role in translation elongation, likely via the basic thumb, but has little impact on ribosomal subunit levels. Hpm1 is therefore a multifunctional methyltransferase with independent roles in ribosome biogenesis and translation.

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Translational Roles of Elongation Factor 2 Protein Lysine Methylation

Cited by 19 publications

References 58 publications

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

Mechanism and Regulation of Protein Synthesis in Saccharomyces cerevisiae

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

Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

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