Title |
Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations
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Published in |
Human Molecular Genetics, December 2015
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DOI | 10.1093/hmg/ddv619 |
Pubmed ID | |
Authors |
Elena Perli, Annarita Fiorillo, Carla Giordano, Annalinda Pisano, Arianna Montanari, Paola Grazioli, Antonio F. Campese, Patrizio Di Micco, Helen A. Tuppen, Ilaria Genovese, Elena Poser, Carmela Preziuso, Robert W. Taylor, Veronica Morea, Gianni Colotti, Giulia d'Amati |
Abstract |
Mutations in mitochondrial (mt) genes coding for mt-tRNAs are responsible for a range of syndromes, for which no effective treatment is available. We recently showed that the carboxy-terminal domain of human mt-leucyl tRNA synthetase (Cterm) rescues the pathologic phenotype associated either with the m.3243A>G mutation in mt-tRNA(Leu(UUR)) or with mutations in the mt-tRNA(Ile), both of which are aminoacylated by Class I mt-aminoacyl-tRNA synthetases (mt-aaRSs).Here we show, by using the human transmitochondrial cybrid model, that the Cterm is also able to improve the phenotype caused by the m.8344A>G mutation in mt-tRNA(Lys), aminoacylated by a Class II aaRS. Importantly, we demonstrate that the same rescuing ability is retained by two Cterm-derived short peptides, β30_31 and β32_33, which are effective towards both the m.8344A>G and the m.3243A>G mutations. Furthermore, we provide in vitro evidence that these peptides bind with high affinity wild-type and mutant human mt-tRNA(Leu(UUR)) and mt-tRNA(Lys), and stabilize mutant mt-tRNA(Leu(UUR)). In conclusion, we demonstrate that small Cterm-derived peptides can be effective tools to rescue cellular defects caused by mutations in a wide range of mt-tRNAs. |
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Student > Ph. D. Student | 4 | 12% |
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Professor > Associate Professor | 2 | 6% |
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Other | 0 | 0% |
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