Structural analyses of a human lysyl-tRNA synthetase mutant associated with autosomal recessive nonsyndromic hearing impairment
| Autor: | Siqi Wu, Jing Wang, Jintong Zhou, Pengfei Fang, Zhoufei Hei, Zaizhou Liu, Li Zheng |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Lysine-tRNA Ligase Mutant Biophysics Aminoacylation Deafness medicine.disease_cause Crystallography X-Ray Biochemistry 03 medical and health sciences 0302 clinical medicine RNA Transfer Protein biosynthesis medicine Anticodon TRNA aminoacylation Missense mutation Humans Genetic Predisposition to Disease Molecular Biology Genetics Mutation Chemistry Wild type Cell Biology Mitochondria 030104 developmental biology 030220 oncology & carcinogenesis Protein Biosynthesis Transfer RNA bacteria Mutant Proteins Protein Structural Elements |
| Zdroj: | Biochemical and biophysical research communications. 554 |
| ISSN: | 1090-2104 |
| Popis: | Aminoacyl-tRNA synthetases (AARSs) catalyze the ligation of amino acids to their cognate tRNAs and therefore play an essential role in protein biosynthesis in all living cells. The KARS gene in human encodes both cytosolic and mitochondrial lysyl-tRNA synthetase (LysRS). A recent study identified a missense mutation in KARS gene (c.517T > C) that caused autosomal recessive nonsyndromic hearing loss. This mutation led to a tyrosine to histidine (YH) substitution in both cytosolic and mitochondrial LysRS proteins, and decreased their aminoacylation activity to different levels. Here, we report the crystal structure of LysRS YH mutant at a resolution of 2.5 A. We found that the mutation did not interfere with the active center, nor did it cause any significant conformational changes in the protein. The loops involved in tetramer interface and tRNA anticodon binding site showed relatively bigger variations between the mutant and wild type proteins. Considering the differences between the cytosolic and mitochondrial tRNAlyss, we suggest that the mutation triggered subtle changes in the tRNA anticodon binding region, and the interferences were further amplified by the different D and T loops in mitochondrial tRNAlys, and led to a complete loss of the aminoacylation of mitochondrial tRNAlys. |
| Databáze: | OpenAIRE |
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