7YDG
Crystal structure of human SARS2 catalytic domain with a disease related mutation
Summary for 7YDG
| Entry DOI | 10.2210/pdb7ydg/pdb |
| Related | 7YDF |
| Descriptor | Serine--tRNA ligase, mitochondrial (1 entity in total) |
| Functional Keywords | mitochondrial seryl-trna synthetase, ligase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 157639.31 |
| Authors | Wu, S.,Li, P.,Zhou, X.L.,Fang, P. (deposition date: 2022-07-04, release date: 2022-11-02, Last modification date: 2023-11-29) |
| Primary citation | Yu, T.,Zhang, Y.,Zheng, W.Q.,Wu, S.,Li, G.,Zhang, Y.,Li, N.,Yao, R.,Fang, P.,Wang, J.,Zhou, X.L. Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease. Nucleic Acids Res., 50:11755-11774, 2022 Cited by PubMed Abstract: Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654-14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases. PubMed: 36350636DOI: 10.1093/nar/gkac1028 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.2 Å) |
Structure validation
Download full validation report
