ArticleThe Journal of biological chemistry2016
A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces Both Structural and Functional Defects.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 47 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- TARS2 c.470 C > G is a chinese-specific founder mutation in three unrelated families with mitochondrial encephalomyopathy.Orphanet journal of rare diseases · 2024Article
- Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation.Nucleic acids research · 2024Article
- Beyond protein synthesis: non-translational functions of threonyl-tRNA synthetases.Biochemical Society transactions · 2024Review
- Multifaceted roles of t6A biogenesis in efficiency and fidelity of mitochondrial gene expression.Nucleic acids research · 2024Article
- Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Mammalian mitochondrial translation infidelity leads to oxidative stress-induced cell cycle arrest and cardiomyopathy.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- The tRNA identity landscape for aminoacylation and beyond.Nucleic acids research · 2023Review
- RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.Nucleic acids research · 2022Article
- Neurodegenerative disorder and diffuse brain calcifications due toClinical case reports · 2022Article
- Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8.Nucleic acids research · 2022Article
- Knockdown of mitochondrial threonyl-tRNA synthetase 2 inhibits lung adenocarcinoma cell proliferation and induces apoptosis.Bioengineered · 2022Article
- Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants.International journal of molecular sciences · 2021Review
- The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases.Nucleic acids research · 2021Article
- The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases.Genes · 2021Review
- Novel compound heterozygous TARS2 variants in a Chinese family with mitochondrial encephalomyopathy: a case report.BMC medical genetics · 2020Article
- Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation.Nucleic acids research · 2020Article
- Molecular basis for t6A modification in human mitochondria.Nucleic acids research · 2020Article
- Mutations in the mitochondrial tryptophanyl-tRNA synthetase cause growth retardation and progressive leukoencephalopathy.Molecular genetics & genomic medicine · 2019Article
- The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase.Nucleic acids research · 2019Article
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondria require all translational components, including aminoacyl-tRNA synthetases (aaRSs), to complete organelle protein synthesis. Some aaRS mutations cause mitochondrial disorders, including human mitochondrial threonyl-tRNA synthetase (hmtThrRS) (encoded by TARS2), the P282L mutation of which causes mitochondrial encephalomyopathies. However, its catalytic and structural consequences remain unclear. Herein, we cloned TARS2 and purified the wild-type and P282L mutant hmtThrRS. hmtThrRS misactivates non-cognate Ser and uses post-transfer editing to clear erroneously synthesized products. In vitro and in vivo analyses revealed that the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities and a change in the protein structure and/or stability, which might cause reduced catalytic efficiency. We also identified a splicing variant of TARS2 mRNA lacking exons 8 and 9, the protein product of which is targeted into mitochondria. In HEK293T cells, the variant does not dimerize and cannot complement the ThrRS knock-out strain in yeast, suggesting that the truncated protein is inactive and might have a non-canonical function, as observed for other aaRS fragments. The present study describes the aminoacylation and editing properties of hmtThrRS, clarifies the molecular consequences of the P282L mutation, and shows that the yeast ThrRS-deletion model is suitable to test pathology-associated point mutations or alternative splicing variants of mammalian aaRS mRNAs.
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