Pathology-related mutation A7526G (A9G) helps in the understanding of the 3D structural core of human mitochondrial tRNAAsp |
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Authors: | Marie Messmer Agnès Gaudry Marie Sissler Catherine Florentz |
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Institution: | Architecture et Réactivité de l''ARN, Institut de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Université de Strasbourg, 67084 Strasbourg, France |
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Abstract: | More than 130 mutations in human mitochondrial tRNA (mt-tRNA) genes have been correlated with a variety of neurodegenerative and neuromuscular disorders. Their molecular impacts are of mosaic type, affecting various stages of tRNA biogenesis, structure, and/or functions in mt-translation. Knowledge of mammalian mt-tRNA structures per se remains scarce however. Primary and secondary structures deviate from classical tRNAs, while rules for three-dimensional (3D) folding are almost unknown. Here, we take advantage of a myopathy-related mutation A7526G (A9G) in mt-tRNAAsp to investigate both the primary molecular impact underlying the pathology and the role of nucleotide 9 in the network of 3D tertiary interactions. Experimental evidence is presented for existence of a 9-12-23 triple in human mt-tRNAAsp with a strongly conserved interaction scheme in mammalian mt-tRNAs. Mutation A7526G disrupts the triple interaction and in turn reduces aspartylation efficiency. |
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Keywords: | mammalian mitochondria tRNA structure probing in solution pathology-related mutations mitochondrial disorder |
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