Dataset Information

CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.

ABSTRACT: Aminoacyl-tRNA synthetases are ubiquitously expressed proteins that charge tRNAs with their cognate amino acids. By ensuring the fidelity of protein synthesis, these enzymes are essential for the viability of every cell. Yet, mutations in six tRNA synthetases specifically affect the peripheral nerves and cause Charcot-Marie-Tooth (CMT) disease. The CMT-causing mutations in tyrosyl- and glycyl-tRNA synthetases (YARS and GARS, respectively) alter the activity of the proteins in a range of ways (some mutations do not impact charging function, while others abrogate it), making a loss of function in tRNA charging unlikely to be the cause of disease pathology. It is currently unknown which cellular mechanisms are triggered by the mutant enzymes and how this leads to neurodegeneration. Here, by expressing two pathogenic mutations (G240R, P234KY) in Drosophila, we generated a model for GARS-associated neuropathy. We observed compromised viability, and behavioral, electrophysiological and morphological impairment in flies expressing the cytoplasmic isoform of mutant GARS. Their features recapitulated several hallmarks of CMT pathophysiology and were similar to the phenotypes identified in our previously described Drosophila model of YARS-associated neuropathy. Furthermore, CG8316 and CG15599 - genes identified in a retinal degeneration screen to modify mutant YARS, also modified the mutant GARS phenotypes. Our study presents genetic evidence for common mutant-specific interactions between two CMT-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies.

SUBMITTER: Ermanoska B

PROVIDER: S-EPMC4086162 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Publications

CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.

Ermanoska Biljana B Motley William W WW Leitão-Gonçalves Ricardo R Asselbergh Bob B Lee LaTasha H LH De Rijk Peter P Sleegers Kristel K Ooms Tinne T Godenschwege Tanja A TA Timmerman Vincent V Fischbeck Kenneth H KH Jordanova Albena A

Neurobiology of disease 20140505

Aminoacyl-tRNA synthetases are ubiquitously expressed proteins that charge tRNAs with their cognate amino acids. By ensuring the fidelity of protein synthesis, these enzymes are essential for the viability of every cell. Yet, mutations in six tRNA synthetases specifically affect the peripheral nerves and cause Charcot-Marie-Tooth (CMT) disease. The CMT-causing mutations in tyrosyl- and glycyl-tRNA synthetases (YARS and GARS, respectively) alter the activity of the proteins in a range of ways (so ...[more]

PMID: 24807208

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Project description:MotivationSimilarities in core residue packing provide evidence for divergence or convergence not reported using other methods.ResultsWe apply a new method for rapid structure comparison based on Simplicial Neighborhood Analysis of Protein Packing (SNAPP) to the diverse structural classification of proteins (SCOP) alpha/beta-class of protein folds. The procedure identifies inter-residue packing motifs shared by protein pairs from different folds. A threshold of 0.67 A RMSD for all atoms of corresponding residues ensures inclusion of only highly significant similarities comparable with those observed for identical catalytic residues in homologues. Many tertiary packing motifs are shared among the three classical Rossmannoid folds, as well as thousands of other motifs that occur in at least two distinct folds. Merging of neighboring packing motifs facilitated recognition of larger, recurrent substructures or cores. The anti-codon-binding domain of an archeal aminoacyl-tRNA synthetase (aaRS) was discovered to possess a packed core in which eight identical amino acid residues are within 0.55 A RMSD of the comparable structure in the FixJ receiver, a member of the Rossmannoid family that also includes the CheY signaling protein and flavodoxin-like proteins. Further investigation identified close variants of this core in five other Rossmannoid folds, including a functionally relevant core in Class Ia aminoacyl-tRNA synthetases. Although it is possible that the two essentially identical cores in the ProRS anti-codon-binding domain and the FixJ receiver converged to the same structure, the consensus core obtained from the structural and sequence alignments suggests that all the implicated protein folds descended from a simpler ancestral protein in which this core provided nucleotide binding and proto-allosteric functions.AvailabilityPrograms are available at http://staff.vbi.vt.edu/cammer/snapp/download/ImplementationPrograms were written in Perl and c and run under Linux.Contactcammer@vbi.vt.edu.

Dataset Information

CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.

Publications

CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.

Similar Datasets

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