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.
Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations / Perli, Elena; Fiorillo, Annarita; Giordano, Carla; Pisano, Annalinda; Montanari, Arianna; Grazioli, Paola; Campese, Antonio Francesco; DI MICCO, Patrizio; Tuppen, Helen A; Genovese, Ilaria; Poser, Elena; Preziuso, Carmela; Taylor, Robert W; Morea, Veronica; Colotti, Gianni; D'Amati, Giulia. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 25:5(2016), pp. 903-915. [10.1093/hmg/ddv619]
Short peptides from leucyl-tRNA synthetase rescue disease-causing mitochondrial tRNA point mutations
PERLI, ELENAPrimo
;FIORILLO, ANNARITASecondo
;GIORDANO, Carla;PISANO, ANNALINDA;MONTANARI, Arianna;GRAZIOLI, PAOLA;CAMPESE, Antonio Francesco;DI MICCO, PATRIZIO;GENOVESE, ILARIA;POSER, ELENA;D'AMATI, Giulia
Ultimo
2016
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.File | Dimensione | Formato | |
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Perli_Short-peptides_2016.pdf
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Note: https://academic.oup.com/hmg/article/25/5/903/2384592
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