Dataset Information

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast.

ABSTRACT: Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t6A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm5s2U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequence is a subsequent increase in protein aggregates and aberrant morphology. Proteomic analysis of the t6A-deficient strain (sua5 mutant) revealed a global mistranslation leading to protein aggregation without regard to physicochemical properties or t6A-dependent or biased codon usage in parent genes. However, loss of sua5 led to increased expression of soluble proteins for mitochondrial function, protein quality processing/trafficking, oxidative stress response, and energy homeostasis. These results point to a global function for t6A in protein homeostasis very similar to mcm5/s2U modifications.

SUBMITTER: Pollo-Oliveira L

PROVIDER: S-EPMC7072221 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast.

Pollo-Oliveira Leticia L Klassen Roland R Davis Nick N Ciftci Akif A Bacusmo Jo Marie JM Martinelli Maria M DeMott Michael S MS Begley Thomas J TJ Dedon Peter C PC Schaffrath Raffael R de Crécy-Lagard Valérie V

Biomolecules 20200218 2

Modifications found in the Anticodon Stem Loop (ASL) of tRNAs play important roles in regulating translational speed and accuracy. Threonylcarbamoyl adenosine (t6A37) and 5-methoxycarbonyl methyl-2-thiouridine (mcm5s2U34) are critical ASL modifications that have been linked to several human diseases. The model yeast Saccharomyces cerevisiae is viable despite the absence of both modifications, growth is however greatly impaired. The major observed consequen ...[more]

PMID: 32085421

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Project description:Modified nucleotides are prevalent in tRNA. Experimental studies reveal that these covalent modifications play an important role in tuning tRNA function. In this study, molecular dynamics (MD) simulations were used to investigate how modifications alter tRNA dynamics. The X-ray crystal structures of tRNA(Asp), tRNA(Phe), and tRNA(iMet), both with and without modifications, were used as initial structures for 333 ns explicit solvent MD simulations with AMBER. For each tRNA molecule, three independent trajectory calculations were performed, giving an aggregate of 6 μs of total MD across six molecules. The global root-mean-square deviations (RMSD) of atomic positions show that modifications only introduce significant rigidity to the global structure of tRNA(Phe). Interestingly, RMSDs of the anticodon stem-loop (ASL) suggest that modified tRNA has a more rigid structure compared to the unmodified tRNA in this domain. The anticodon RMSDs of the modified tRNAs, however, are higher than those of corresponding unmodified tRNAs. These findings suggest that the rigidity of the anticodon stem-loop is finely tuned by modifications, where rigidity in the anticodon arm is essential for tRNA translocation in the ribosome, and flexibility of the anticodon is important for codon recognition. Sugar pucker and water residence time of pseudouridines in modified tRNAs and corresponding uridines in unmodified tRNAs were assessed, and the results reinforce that pseudouridine favors the 3'-endo conformation and has a higher tendency to interact with water. Principal component analysis (PCA) was used to examine correlated motions in tRNA. Additionally, covariance overlaps of PCAs were compared for trajectories of the same molecule and between trajectories of modified and unmodified tRNAs. The comparison suggests that modifications alter the correlated motions. For the anticodon bases, the extent of stacking was compared between modified and unmodified molecules, and only unmodified tRNA(Asp) has significantly higher percentage of stacking time. Overall, the simulations reveal that the effect of covalent modification on tRNA dynamics is not simple, with modifications increasing flexibility in some regions of the structure and increasing rigidity in other regions.

Dataset Information

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast.

Publications

Loss of Elongator- and KEOPS-Dependent tRNA Modifications Leads to Severe Growth Phenotypes and Protein Aggregation in Yeast.

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