Breaking a single hydrogen bond in the mitochondrial tRNA Phe ‐PheRS complex leads to phenotypic pleiotropy of human disease
| Autor: | Zofia M.A. Chrzanowska-Lightowlers, Ekaterine Kartvelishvili, Dmitry Tworowski, Moshe Peretz, John H. Livingston, Mark Safro |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetics Chemistry Mutant Protein Data Bank (RCSB PDB) Aminoacylation Cell Biology Biochemistry 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Pleiotropy 030220 oncology & carcinogenesis Transfer RNA Mutation (genetic algorithm) Molecular Biology Gene Binding domain |
| Zdroj: | The FEBS Journal. 287:3814-3826 |
| ISSN: | 1742-4658 1742-464X |
| Popis: | Various pathogenic variants in both mitochondrial tRNAPhe and Phenylalanyl-tRNA synthetase mitochondrial protein coding gene (FARS2) gene encoding for the human mitochondrial PheRS have been identified and associated with neurological and/or muscle-related pathologies. An important Guanine-34 (G34)A anticodon mutation associated with myoclonic epilepsy with ragged red fibers (MERRF) syndrome has been reported in hmit-tRNAPhe . The majority of G34 contacts in available aaRSs-tRNAs complexes specifically use that base as an important tRNA identity element. The network of intermolecular interactions providing its specific recognition also largely conserved. However, their conservation depends also on the invariance of the residues in the anticodon binding domain (ABD) of human mitochondrial Phenylalanyl-tRNA synthetase (hmit-PheRS). A defect in recognition of the anticodon of tRNAPhe may happen not only because of G34A mutation, but also due to mutations in the ABD. Indeed, a pathogenic mutation in FARS2 has been recently reported in a 9-year-old female patient harboring a p.Asp364Gly mutation. Asp364 is hydrogen bonded (HB) to G34 in WT hmit-PheRS. Thus, there are two pathogenic variants disrupting HB between G34 and Asp364: one is associated with G34A mutation, and the other with Asp364Gly mutation. We have measured the rates of tRNAPhe aminoacylation catalyzed by WT hmit-PheRS and mutant enzymes. These data ranked the residues making a HB with G34 according to their contribution to activity and the signal transduction pathway in the hmit-PheRS-tRNAPhe complex. Furthermore, we carried out extensive MD simulations to reveal the interdomain contact topology on the dynamic trajectories of the complex, and gaining insight into the structural and dynamic integrity effects of hmit-PheRS complexed with tRNAPhe . DATABASE: Structural data are available in PDB database under the accession number(s): 3CMQ, 3TUP, 5MGH, 5MGV. |
| Databáze: | OpenAIRE |
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