Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Wobble tRNA modification and hydrophilic amino acid patterns dictate protein fate.

ABSTRACT: Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm⁵s² wobble uridine tRNA modification (U₃₄-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U₃₄-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U₃₄-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis.

SUBMITTER: Rapino F

PROVIDER: S-EPMC8050329 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Wobble tRNA modification dependent protein aggregates modification

Project description:We want to assess the features of proteins whose aggregation depends on defects in traslation by the loss of the mcm5s2 modification on the urifdine in position 34 of some tRNAs.

2021-02-24 | PXD019590 | Pride

Wobble tRNA modification dependent proteome

Project description:We want to assess the features of proteins whose translation depends on the mcm5s2 modification of urifdine in position 34 of some tRNAs.

2021-02-24 | PXD019620 | Pride

Cbr1 is a Dph3 reductase required for the tRNA wobble uridine modification.

Project description:Diphthamide and the tRNA wobble uridine modifications both require diphthamide biosynthesis 3 (Dph3) protein as an electron donor for the iron-sulfur clusters in their biosynthetic enzymes. Here, using a proteomic approach, we identified Saccharomyces cerevisiae cytochrome b5 reductase (Cbr1) as a NADH-dependent reductase for Dph3. The NADH- and Cbr1-dependent reduction of Dph3 may provide a regulatory linkage between cellular metabolic state and protein translation.

| S-EPMC5110365 | biostudies-literature

Determinants of the CmoB carboxymethyl transferase utilized for selective tRNA wobble modification.

Project description:Enzyme-mediated modifications at the wobble position of tRNAs are essential for the translation of the genetic code. We report the genetic, biochemical and structural characterization of CmoB, the enzyme that recognizes the unique metabolite carboxy-S-adenosine-L-methionine (Cx-SAM) and catalyzes a carboxymethyl transfer reaction resulting in formation of 5-oxyacetyluridine at the wobble position of tRNAs. CmoB is distinctive in that it is the only known member of the SAM-dependent methyltransferase (SDMT) superfamily that utilizes a naturally occurring SAM analog as the alkyl donor to fulfill a biologically meaningful function. Biochemical and genetic studies define the in vitro and in vivo selectivity for Cx-SAM as alkyl donor over the vastly more abundant SAM. Complementary high-resolution structures of the apo- and Cx-SAM bound CmoB reveal the determinants responsible for this remarkable discrimination. Together, these studies provide mechanistic insight into the enzymatic and non-enzymatic feature of this alkyl transfer reaction which affords the broadened specificity required for tRNAs to recognize multiple synonymous codons.

| S-EPMC4482062 | biostudies-literature

Hydrophobic, hydrophilic, and charged amino acid networks within protein.

Project description:The native three-dimensional structure of a single protein is determined by the physicochemical nature of its constituent amino acids. The 20 different types of amino acids, depending on their physicochemical properties, can be grouped into three major classes: hydrophobic, hydrophilic, and charged. The anatomy of the weighted and unweighted networks of hydrophobic, hydrophilic, and charged residues separately for a large number of proteins were studied. Results showed that the average degree of the hydrophobic networks has a significantly larger value than that of hydrophilic and charged networks. The average degree of the hydrophilic networks is slightly higher than that of the charged networks. The average strength of the nodes of hydrophobic networks is nearly equal to that of the charged network, whereas that of hydrophilic networks has a smaller value than that of hydrophobic and charged networks. The average strength for each of the three types of networks varies with its degree. The average strength of a node in a charged network increases more sharply than that of the hydrophobic and hydrophilic networks. Each of the three types of networks exhibits the "small-world" property. Our results further indicate that the all-amino-acids networks and hydrophobic networks are of assortative type. Although most of the hydrophilic and charged networks are of the assortative type, few others have the characteristics of disassortative mixing of the nodes. We have further observed that all-amino-acids networks and hydrophobic networks bear the signature of hierarchy, whereas the hydrophilic and charged networks do not have any hierarchical signature.

| S-EPMC1914426 | biostudies-literature

Elongator function in tRNA wobble uridine modification is conserved between yeast and plants.

Project description:Based on studies in yeast and mammalian cells the Elongator complex has been implicated in functions as diverse as histone acetylation, polarized protein trafficking and tRNA modification. Here we show that Arabidopsis mutants lacking the Elongator subunit AtELP3/ELO3 have a defect in tRNA wobble uridine modification. Moreover, we demonstrate that yeast elp3 and elp1 mutants expressing the respective Arabidopsis Elongator homologues AtELP3/ELO3 and AtELP1/ELO2 assemble integer Elongator complexes indicating a high degree of structural conservation. Surprisingly, in vivo complementation studies based on Elongator-dependent tRNA nonsense suppression and zymocin tRNase toxin assays indicated that while AtELP1 rescued defects of a yeast elp1 mutant, the most conserved Elongator gene AtELP3, failed to complement an elp3 mutant. This lack of complementation is due to incompatibility with yeast ELP1 as coexpression of both plant genes in an elp1 elp3 yeast mutant restored Elongator's tRNA modification function in vivo. Similarly, AtELP1, not ScELP1 also supported partial complementation by yeast-plant Elp3 hybrids suggesting that AtElp1 has less stringent sequence requirements for Elp3 than ScElp1. We conclude that yeast and plant Elongator share tRNA modification roles and propose that this function might be conserved in Elongator from all eukaryotic kingdoms of life.

| S-EPMC2904499 | biostudies-literature

Loss of wobble uridine modification in tRNA anticodons interferes with TOR pathway signaling.

Project description:Previous work in yeast has suggested that modification of tRNAs, in particular uridine bases in the anticodon wobble position (U34), is linked to TOR (target of rapamycin) signaling. Hence, U34 modification mutants were found to be hypersensitive to TOR inhibition by rapamycin. To study whether this involves inappropriate TOR signaling, we examined interaction between mutations in TOR pathway genes (tip41∆, sap190∆, ppm1∆, rrd1∆) and U34 modification defects (elp3∆, kti12∆, urm1∆, ncs2∆) and found the rapamycin hypersensitivity in the latter is epistatic to drug resistance of the former. Epistasis, however, is abolished in tandem with a gln3∆ deletion, which inactivates transcription factor Gln3 required for TOR-sensitive activation of NCR (nitrogen catabolite repression) genes. In line with nuclear import of Gln3 being under control of TOR and dephosphorylation by the Sit4 phosphatase, we identify novel TOR-sensitive sit4 mutations that confer rapamycin resistance and importantly, mislocalise Gln3 when TOR is inhibited. This is similar to gln3∆ cells, which abolish the rapamycin hypersensitivity of U34 modification mutants, and suggests TOR deregulation due to tRNA undermodification operates through Gln3. In line with this, loss of U34 modifications (elp3∆, urm1∆) enhances nuclear import of and NCR gene activation (MEP2, GAP1) by Gln3 when TOR activity is low. Strikingly, this stimulatory effect onto Gln3 is suppressed by overexpression of tRNAs that usually carry the U34 modifications. Collectively, our data suggest that proper TOR signaling requires intact tRNA modifications and that loss of U34 modifications impinges on the TOR-sensitive NCR branch via Gln3 misregulation.

| S-EPMC5349137 | biostudies-literature

Antibody production relies on the tRNA inosine wobble modification to meet biased codon demand.

Project description:Antibodies are produced at high rates to provide immunoprotection, which puts pressure on the B cell translational machinery. Here, we identified a pattern of codon usage conserved across antibody genes. One feature thereof is the hyperutilization of codons that lack genome-encoded Watson-Crick transfer RNAs (tRNAs), instead relying on the posttranscriptional tRNA modification inosine (I34), which expands the decoding capacity of specific tRNAs through wobbling. Antibody-secreting cells had increased I34 levels and were more reliant on I34 for protein production than naïve B cells. Furthermore, antibody I34-dependent codon usage may influence B cell passage through regulatory checkpoints. Our work elucidates the interface between the tRNA pool and protein production in the immune system and has implications for the design and selection of antibodies for vaccines and therapeutics.

| S-EPMC10954030 | biostudies-literature

Archaeal Elp3 catalyzes tRNA wobble uridine modification at C5 via a radical mechanism.

Project description:Approximately 25% of cytoplasmic tRNAs in eukaryotic organisms have the wobble uridine (U34) modified at C5 through a process that, according to genetic studies, is carried out by the eukaryotic Elongator complex. Here we show that a single archaeal protein, the homolog of the third subunit of the eukaryotic Elongator complex (Elp3), is able to catalyze the same reaction. The mechanism of action by Elp3 described here represents unprecedented chemistry performed on acetyl-CoA.

| S-EPMC4479141 | biostudies-other

Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival.

Project description:tRNA nucleosides are extensively modified to ensure their proper function in translation. However, many of the enzymes responsible for tRNA modifications in mammals await identification. Here, we show that human AlkB homolog 8 (ABH8) catalyzes tRNA methylation to generate 5-methylcarboxymethyl uridine (mcm(5)U) at the wobble position of certain tRNAs, a critical anticodon loop modification linked to DNA damage survival. We find that ABH8 interacts specifically with tRNAs containing mcm(5)U and that purified ABH8 complexes methylate RNA in vitro. Significantly, ABH8 depletion in human cells reduces endogenous levels of mcm(5)U in RNA and increases cellular sensitivity to DNA-damaging agents. Moreover, DNA-damaging agents induce ABH8 expression in an ATM-dependent manner. These results expand the role of mammalian AlkB proteins beyond that of direct DNA repair and support a regulatory mechanism in the DNA damage response pathway involving modulation of tRNA modification.

| S-EPMC2863699 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data