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The dual methyltransferase METTL13 targets N-terminus and Lys55 of eEF1A and regulates codon-specific translation rates

ABSTRACT: The dual methyltransferase METTL13 targets N-terminus and Lys55 of eEF1A and regulates codon-specific translation rates

PROVIDER: PRJNA408071 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6053330.fastq.gz	Fastqsanger.gz
	SRR6053331.fastq.gz	Fastqsanger.gz
	SRR6053332.fastq.gz	Fastqsanger.gz
	SRR6053333.fastq.gz	Fastqsanger.gz
	SRR6053334.fastq.gz	Fastqsanger.gz

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Similar Datasets

The dual methyltransferase METTL13 targets N-terminus and Lys55 of eEF1A and regulates codon-specific translation rates

Project description:Eukaryotic elongation factor 1 alpha (eEF1A) delivers aminoacyl-tRNA to the ribosome and thereby plays a key role in protein synthesis. Human eEF1A is post-translationally methylated on several lysine residues as well as on the N-terminus and until recently the responsible methyltransferases were largely elusive. Using mass spectrometry based screens, gene targeted cells and in vitro enzymology we identify the human methyltransferase like proteins 13 (METTL13), which contains two distinct methyltransferase domains, as an enzyme catalyzing both dimethylation of Lys55 and trimethylation of the N-terminus of eEF1A. Moreover, through ribosome profiling we demonstrate that loss of METTL13 function alters translation dynamics and results in changed translation rate of specific codons. In line with the established descriptive nomenclature for this type of enzymes we suggest that METTL13 is redubbed eEF1A dual methyltransferase (eEF1A-DMT / EEF1ADMT).

2018-07-04 | GSE104033 | GEO

The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.

Project description: Not available

| S-EPMC6109062 | biostudies-literature

The novel lysine specific methyltransferase METTL21B affects mRNA translation through inducible and dynamic methylation of Lys-165 in human eukaryotic elongation factor 1 alpha (eEF1A)

Project description:Lysine methylation is abundant on histone proteins, representing a dynamic regulator of chromatin state and gene activity, but is also frequent on many nonhistone proteins, including eukaryotic elongation factor 1 alpha (eEF1A). However, the functional significance of eEF1Amethylation remains obscure and it has remained unclear whether eEF1A methylation is dynamic and subject to active regulation. We here demonstrate, using a wide range of in vitro and in vivo approaches, that the previously uncharacterized human methyltransferase METTL21B specifically targets Lys-165 in eEF1A in an aminoacyl-tRNA- and GTP-dependent manner. Interestingly, METTL21B mediated eEF1A methylation showed strong variation across different tissues and cell lines, and was induced by altering growth conditions or by treatment with certain ER-stress-inducing drugs, concomitant with an increase in METTL21B gene expression. Moreover, genetic ablation of METTL21B function in mammalian cells caused substantial alterations in mRNA translation, as measured by ribosome profiling. A non-canonical function for eEF1A in organization of the cellular cytoskeleton has been reported, and interestingly, METTL21B accumulated in centrosomes, in addition to the expected cytosolic localization. In summary, the present study identifies METTL21B as the enzyme responsible for methylation of eEF1A on Lys-165 and shows that this modification is dynamic, inducible and likely of regulatory importance.

2017-01-05 | GSE93133 | GEO

METTL13 modulates mRNA translation through methylation of eEF1A at Lys55 and the N-terminus

Project description:The experiment aimed at identifying lysine methylation dependent interactions for eEF1A. FLAG-tagged wild type eEF1A and a methylation deficient mutant, carrying lysine-to-arginine mutations of the well-established methylation sites (Lys36, Lys55, Lys79, Lys165 and Lys318) were overexpressed in HEK-293 cells and co-purifying proteins were quantified using the MaxLFQ algorithm. FLAG-tagged

2018-07-04 | PXD009895 | Pride

Optimization of codon translation rates via tRNA modifications maintains proteome integrity

Project description:Optimization of codon translation rates via tRNA modifications maintains proteome integrity

| PRJNA279785 | ENA

Mechanisms of site-specific methylation by a highly conserved elongation factor 1A lysine methyltransferase

Project description:Translation elongation factor 1A (eEF1A) is an essential and highly conserved protein required for protein synthesis in eukaryotes. In both Saccharomyces cerevisiae and human, five different methyltransferase enzymes methylate specific residues on eEF1A, making eEF1A the eukaryotic protein targeted by the highest number of dedicated methyltransferases. eEF1A methyltransferases are highly selective enzymes, only targeting eEF1A and each targeting just one or two specific residues in eEF1A. However, the mechanism of this selectivity remains poorly understood. Here we have used AlphaFold modelling in combination with crosslinking mass spectrometry (XL-MS) and enzyme mutagenesis to reveal how S. cerevisiae elongation factor methyltransferase 4 (Efm4) specifically methylates eEF1A at K316. We find that a unique beta-hairpin motif, which extends out from the core methyltransferase fold, is important for methylation of eEF1A K316 in vitro. An alanine mutation of a single residue on this beta-hairpin, F212, significantly reduces Efm4 activity in vitro and in yeast cells. We show that the equivalent residue in human eEF1A-KMT2 (METTL10), F220, is also important for its activity towards eEF1A in vitro. Lastly, we find that phosphorylation of eEF1A at S314 negatively crosstalks with Efm4-mediated methylation of K316. Our findings demonstrate how protein methyltransferases can be being highly selective towards a single residue on a single protein.

2024-01-03 | PXD042599 | Pride

Methylation of human eukaryotic elongation factor alpha (eEF1A) by a member of a novel protein lysine methyltransferase family modulates mRNA translation

Project description:Many cellular proteins are post-translationally modified by methylation of lysine residues. This has been most intensively studied in the case of histone proteins, where lysine methylations in the flexible tails are determinants of chromatin state and gene expression. Lysine methylations on non-histone proteins are also frequent, but in most cases the functional significance of the methylation event, as well as the identity of the responsible lysine (K) specific methyltransferase (KMT), remain unknown. While the majority of identified human KMTs belong to the SET (Su(var)3-9, Enhancer-of-zeste, Trithorax)-domain class of methyltransferases (MTases), several recently discovered KMTs belong to a different MTase class, the seven-beta-strand (7BS) MTases. Here, we have investigated an uncharacterized human 7BS MTase currently annotated as being part of the endothelin converting enzyme 2 (ECE2). However, transcriptomics data indicate that this MTase is not part of ECE2, and should be considered a separate protein. Combining in vitro enzymology and analyses of knockout cells, we demonstrate that this MTase efficiently methylates K36 in eukaryotic translation elongation factor 1 alpha (eEF1A) in vitro and in vivo. We suggest that this novel KMT is named eEF1A-KMT4 (gene name EEF1AKMT4), in agreement with the recently established nomenclature. Furthermore, by ribosome profiling we show that the absence of K36 methylation affects translation dynamics and changes translation speed of distinct codons. Finally, we demonstrate that eEF1A-KMT4 is part of a novel family of human KMTs, defined by a shared sequence motif in the active site, and we show the importance of this motif for catalytic activity.

2017-05-23 | GSE97140 | GEO

Expression data from Saccharomyces cerevisiae with eEF1A overexpression

Project description:The canonical role of eEF1A is to deliver the aminoacyl tRNA to the ribosome, we have used the yeast model system to investigate further roles for this protein. We used microarray to study the transcriptomic effects of elevated levels of eEF1A on yeast cells during log phase growth

2016-10-29 | GSE89286 | GEO

Dedicated chaperone at the ribosome safeguards the proteostasis network during eEF1A biogenesis

Project description:Cotranslational protein folding depends on general chaperones that engage highly diverse nascent chains at the ribosomes. Here we find that the universal cotranslational machinery adapts to accommodate the challenging biogenesis of abundantly expressed eukaryotic translation elongation factor 1A (eEF1A). During eEF1A synthesis, chaperone Chp1 is recruited to the ribosome with the help of the nascent polypeptide-associated complex (NAC), where it safeguards eEF1A biogenesis. Aberrant eEF1A production triggers instant proteolysis, widespread protein aggregation, activation of Hsf1 stress transcription and compromises cellular fitness. The expression of pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy is protected by Chp1. Thus, eEF1A is a difficult to fold protein that necessitates dedicated folding factor Chp1 at the ribosomal tunnel exit to protect the eukaryotic cell from proteostasis collapse.

2024-01-16 | GSE221651 | GEO

METTL13 modulates mRNA translation through methylation of eEF1A at Lys55 and the N-terminus, part 2

Project description:The experiment aimed at characterizing the methylation status of eEF1A in cells (HeLa) stressed using a panel of drugs including anisomycin, cycloheximide, 4NQO and adenosine dialdehyde (AdOx).

2018-07-04 | PXD009914 | Pride

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