On January 25, the international scientific journal《Journal of Biological Chemistry》online published the new work from Enduo Wang’s group in Institute of Biochemistry and Cell Biology etc. entiled “A Human Disease-causing Point Mutation in Mitochondrial Threonyl-tRNA Synthetase Induces both Structural and Functional Defects”
Mitochondria functional disorders are related with serials of diseases. Human mitochondrial aminoacyl-tRNA synthetases are key components and synthesized in cytoplasm and transported into mitochondria by mitochondria target sequence (MTS). Aminoacyl-tRNA synthetases (aaRSs) catalyze amino acids and tRNA to produce aminoacyl-tRNA for protein synthesis. Meantime, aaRSs specific recognize the cognate amino acid and tRNA substrates to provide right substrates for protein synthesis and control the quality of protein synthesis. Recently study found that a P282L mutation in mitochondrial ThrRS (hmtThrRS) leads to mitochondrial encephalomyopathy. The infant containing the mutant died in a few months after born. However, the disease-causing mechanism is not clear. Moreover, how hmtThrRS recognizes its substrate and maintains the fidelity of protein synthesis needs to be illustrated.
Under the guidance of Prof. Enduo Wang, Ph. D candidates Yong Wang, Zhirong Ruan and Dr. Xiaolong Zhou by the methods of biochemistry and molecular biology found that hmtThrRS mis-activates non-cognate Ser and uses post-transfer editing to clear mischarged hmttRNAThr to control the quality of the materials for protein synthesis in ribosome. The interaction mechanism between hmtThrRS and its cognate tRNA is further understood. The P282L mutation of hmtThrRS induces a decrease in Thr activation, aminoacylation, and proofreading activities and its stability, then these changes might decrease catalytic rate and fidelity of protein biosynthesis. These results improve our understanding of the quality control mechanism of mitochondrial protein synthesis and reveal the pathogenesis of mitochondrial encephalomyopathy caused by P282L mutation of hmtThrRS. Meantime, we also identify a splicing variant of TARS2 encoding hmtThrRS-SV. The results by immunofluorescence and immune precipitation showed that hmtThrRS and hmtThrRS-SV are all located in mitochondria. HmtThrRS forms functional homodimer. However, hmtThrRS-SV cannot form homodimer, suggesting that the truncated protein might have a non-canonical function, raising an important scientific question to be answered.
This work was supported by grants from the National Key Basic Research Foundation of China; the Natural Science Foundation of China; and the Committee of Science and Technology in Shanghai; Youth Innovation Promotion Association, CAS (to Xiao-Long Zhou).
Figure. Conservation and structure of hmtThrRS Pro282 (Image provided by Wang Enduo’s Group)
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