A natural non-Watson–Crick base pair in human mitochondrial tRNAThr causes structural and functional susceptibility to local mutations
Autor: | Xiao-Long Zhou, En-Duo Wang, Wen-Qiang Zheng, Quan-Quan Ji, Yong Wang, Qi-Yu Zeng |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
RNA Mitochondrial Base pair Saccharomyces cerevisiae Aminoacylation medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Anticodon Threonine-tRNA Ligase Genetics medicine Humans Nucleotide Transfer RNA Aminoacylation Base Pairing RNA Transfer Thr chemistry.chemical_classification Mutation biology Nucleic Acid Enzymes biology.organism_classification Mitochondria 030104 developmental biology chemistry RNA editing Transfer RNA RNA Editing 030217 neurology & neurosurgery |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | Six pathogenic mutations have been reported in human mitochondrial tRNAThr (hmtRNAThr); however, the pathogenic molecular mechanism remains unclear. Previously, we established an activity assay system for human mitochondrial threonyl-tRNA synthetase (hmThrRS). In the present study, we surveyed the structural and enzymatic effects of pathogenic mutations in hmtRNAThr and then focused on m.15915 G > A (G30A) and m.15923A > G (A38G). The harmful evolutionary gain of non-Watson–Crick base pair A29/C41 caused hmtRNAThr to be highly susceptible to mutations disrupting the G30–C40 base pair in various ways; for example, structural integrity maintenance, modification and aminoacylation of tRNAThr, and editing mischarged tRNAThr. A similar phenomenon was observed for hmtRNATrp with an A29/C41 non-Watson–Crick base pair, but not in bovine mtRNAThr with a natural G29–C41 base pair. The A38G mutation caused a severe reduction in Thr-acceptance and editing of hmThrRS. Importantly, A38 is a nucleotide determinant for the t6A modification at A37, which is essential for the coding properties of hmtRNAThr. In summary, our results revealed the crucial role of the G30–C40 base pair in maintaining the proper structure and function of hmtRNAThr because of A29/C41 non-Watson–Crick base pair and explained the molecular outcome of pathogenic G30A and A38G mutations. |
Databáze: | OpenAIRE |
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