Disease-associated mutations in a bifunctional aminoacyl-tRNA synthetase gene elicit the integrated stress response
| Autor: | Karin Musier-Forsyth, Ronald C. Wek, Sheree A. Wek, Marina Bakhtina, William A. Cantara, Nathan T. Kudlapur, Danni Jin |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
multisynthetase complex ATF4 activating transcription factor 4 aminoacyl-tRNA synthetases medicine.disease_cause Biochemistry chemistry.chemical_compound RNA Transfer enzyme kinetics AIMP ARS-complex interacting multifunctional protein PERK PKR-like endoplasmic reticulum kinase glutamyl-prolyl-tRNA synthetase Protein biosynthesis Amino Acids CD circular dichroism Amino acid activation chemistry.chemical_classification Mutation FA fluorescence anisotropy Editors' Pick integrated stress response ARS aminoacyl-tRNA synthetase Amino acid Cell biology GAIT gamma interferon-activated inhibition of translation Bone Diseases compound-heterozygous mutations Research Article SEC size-exclusion chromatography PRS prolyl-tRNA synthetase Mutation Missense tRNA charging Amino Acyl-tRNA Synthetases Editors' Pick Highlight MSC multisynthetase complex Stress Physiological genetic disease aaRSs aminoacyl-tRNA synthetases GST glutathione-S-transferase Diabetes Mellitus medicine Integrated stress response Humans EPRS glutamyl-prolyl-tRNA synthetase Molecular Biology CHOP C/EBP-homologous protein ISR integrated stress response MALS multiangle laser light scattering GCN2 general control nonderepressible 2 Aminoacyl tRNA synthetase Genetic Diseases Inborn Cell Biology stress response EPRS TRNA binding WT wild-type compound heterozygous mutations Glutamate-tRNA Ligase HEK293 Cells Amino Acid Substitution chemistry DTT dithiothreitol Protein Biosynthesis Aminoacyl-tRNA synthetase endoplasmic reticulum stress (ER stress) ERS glutamyl-tRNA synthetase |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X 0021-9258 |
| Popis: | Aminoacyl-tRNA synthetases (ARSs) catalyze the charging of specific amino acids onto cognate tRNAs, an essential process for protein synthesis. Mutations in ARSs are frequently associated with a variety of human diseases. The human EPRS1 gene encodes a bifunctional glutamyl-prolyl-tRNA synthetase (EPRS) with two catalytic cores and appended domains that contribute to nontranslational functions. In this study, we report compound heterozygous mutations in EPRS1, which lead to amino acid substitutions P14R and E205G in two patients with diabetes and bone diseases. While neither mutation affects tRNA binding or association of EPRS with the multisynthetase complex, E205G in the glutamyl-tRNA synthetase (ERS) region of EPRS is defective in amino acid activation and tRNAGlu charging. The P14R mutation induces a conformational change and altered tRNA charging kinetics in vitro. We propose that the altered catalytic activity and conformational changes in the EPRS variants sensitize patient cells to stress, triggering an increased integrated stress response (ISR) that diminishes cell viability. Indeed, patient-derived cells expressing the compound heterozygous EPRS show heightened induction of the ISR, suggestive of disruptions in protein homeostasis. These results have important implications for understanding ARS-associated human disease mechanisms and development of new therapeutics. |
| Databáze: | OpenAIRE |
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