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malfunction
EPRS-haploid (Eprs+/-) mice show enhanced viremia and inflammation and delayed viral clearance
evolution
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many bacterial GluRS are capable of recognizing two tRNA substrates: tRNAGlu and tRNAGln, e.g. GluRS from such as Bacillus subtilis, Thermosynechococcus elongatus, and Mycobacterium tuberculosis. In bacteria such as Escherichia coli and Thermus thermophilus that possess glutaminyl-tRNA synthetase (GlnRS), the cognate aminoacylating enzyme for tRNAGln, GluRS exclusively glutamylates tRNAGlu. tRNA-GluRS interaction in bacteria is also associated with phylum-specific idiosyncrasies, structure-function analysis, overview
evolution
the enzyme evolved by gene duplication in early eukaryotes from a nondiscriminating glutamyl-tRNAsynthetase (GluRSND, EC 6.1.1.24) that aminoacylates both tRNAGln and tRNAGlu with glutamate. This ancient GluRS also separately differentiated to exclude tRNAGln as a substrate, and the resulting discriminating GluRS and GlnRS further acquired additional protein domains assisting function in cis (the GlnRS N-terminal Yqey domain) or in trans (the Arc1p protein associating with GluRS), evolutionary modeling, detailed overview. These added domains are absent in contemporary bacterial GlnRS and GluRS. The eukaryote-specific protein domains substantially influence amino acid binding, tRNA binding and aminoacylation efficiency, but they play no role in either specific nucleotide readout or discrimination against noncognate tRNA. Eukaryotic tRNAGln and tRNAGlu recognition determinants are found in equivalent positions and aremutually exclusive to a significant degree, with key nucleotides located adjacent to portions of the protein structure that differentiated during the evolution of archaeal nondiscriminating GluRS to GlnRS. The added eukaryotic domains arose in response to distinctive selective pressures associated with the greater complexity of the eukaryotic translational apparatus. The affinity of GluRS for glutamate is significantly increased when Arc1p is not associated with the enzyme. GluRS and GlnRS are among just four aaRS families (the others are arginyl-tRNA synthetase and class I LysRS) that require the presence of tRNA for synthesis of the aminoacyl adenylate reaction intermediate. Each cytoplasmic GlxRS-tRNA pair has fully lost the ancestral nondiscriminating activity in the course of coevolution, and the more stringent specificities of Saccharomyces cerevisiae GlnRS and GluRS arise from the conserved catalytic portions of each enzyme
evolution
the structures of the active sites of bacterial and mammalian GluRSs differ significantly
evolution
the tRNA binding site is less conserved than either the Glu or the ATP binding site. Certain amino acids, including Arg147, which interacts with the tRNAGlu C74 phosphate, and Asp44 and Arg47, which interact with the 2'-hydroxyl group of C75, as well as Tyr187 and Thr43, which interact with the adenosine base and the 5'-hydroxyl group of A76, are strictly conserved
evolution
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the enzyme evolved by gene duplication in early eukaryotes from a nondiscriminating glutamyl-tRNAsynthetase (GluRSND, EC 6.1.1.24) that aminoacylates both tRNAGln and tRNAGlu with glutamate. This ancient GluRS also separately differentiated to exclude tRNAGln as a substrate, and the resulting discriminating GluRS and GlnRS further acquired additional protein domains assisting function in cis (the GlnRS N-terminal Yqey domain) or in trans (the Arc1p protein associating with GluRS), evolutionary modeling, detailed overview. These added domains are absent in contemporary bacterial GlnRS and GluRS. The eukaryote-specific protein domains substantially influence amino acid binding, tRNA binding and aminoacylation efficiency, but they play no role in either specific nucleotide readout or discrimination against noncognate tRNA. Eukaryotic tRNAGln and tRNAGlu recognition determinants are found in equivalent positions and aremutually exclusive to a significant degree, with key nucleotides located adjacent to portions of the protein structure that differentiated during the evolution of archaeal nondiscriminating GluRS to GlnRS. The added eukaryotic domains arose in response to distinctive selective pressures associated with the greater complexity of the eukaryotic translational apparatus. The affinity of GluRS for glutamate is significantly increased when Arc1p is not associated with the enzyme. GluRS and GlnRS are among just four aaRS families (the others are arginyl-tRNA synthetase and class I LysRS) that require the presence of tRNA for synthesis of the aminoacyl adenylate reaction intermediate. Each cytoplasmic GlxRS-tRNA pair has fully lost the ancestral nondiscriminating activity in the course of coevolution, and the more stringent specificities of Saccharomyces cerevisiae GlnRS and GluRS arise from the conserved catalytic portions of each enzyme
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evolution
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the tRNA binding site is less conserved than either the Glu or the ATP binding site. Certain amino acids, including Arg147, which interacts with the tRNAGlu C74 phosphate, and Asp44 and Arg47, which interact with the 2'-hydroxyl group of C75, as well as Tyr187 and Thr43, which interact with the adenosine base and the 5'-hydroxyl group of A76, are strictly conserved
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metabolism
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the sensitivity to oxidation of GluRS1 might provide a means to regulate tetrapyrrole and protein biosynthesis in response to extreme changes in both the redox and heme status of the cell via a single enzyme. The glutamate moiety of Glu-tRNAGlu is transformed to glutamate semialdehyde by the glutamyl-tRNA reductase and is subsequently transformed to 4-aminolevulinic acid, the universal precursor of tetrapyrroles, by the glutamate semialdehyde amidotransferase
metabolism
under conditions of stress, several MSC components, including EPRS, methionyl-tRNA synthetase (MRS), lysyl-tRNA synthetase (KRS), AIMP1 and AIMP2, are released from the complex through post-translational modifications to exert activities during non-translational events such as inflammation, cell metabolism, angiogenesis, and tumorigenesis. Phosphorylation is the critical regulatory mechanism that determines the non-translational function of ARSs in cells, overview
metabolism
under conditions of stress, several MSC components, including EPRS, methionyl-tRNA synthetase (MRS), lysyl-tRNA synthetase (KRS), AIMP1 and AIMP2, are released from the complex through post-translational modifications to exert activities during non-translational events such as inflammation, cell metabolism, angiogenesis, and tumorigenesis. Phosphorylation is the critical regulatory mechanism that determines the non-translational function of ARSs in cells, overview
physiological function
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cytoplasmic glutamyl tRNA synthetase gene ers1 is an Moc3 interacting element. Cell growth is moderately affected by cGluRS over-expression under de-repressed conditions. Over-expression of ers1 stimulates sexual differentiation
physiological function
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mitochondrial glutamyl tRNA synthetase gene ers2 is an Moc3 interacting element. Cell growth is severely affected by ers2 over-expression under de-repressed conditions. Under repressed conditions, the cells multiply quickly. In addition, cells over-expressing ers2 show higher mating efficiency than control
physiological function
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in cells containing glutaminyl-tRNA synthetase, GlnRS, discriminating GluRS specifically aminoacylates tRNAGlu with glutamate. One of two GluRSs from the extremophile Acidithiobacillus ferrooxidans, is inactivated when intracellular heme is elevated suggesting a specific role for GluRS1 in the regulation of tetrapyrrole biosynthesis
physiological function
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mechanism of translation control of enzyme EPRS involving increased translation initiation stringency during stress-induced eIF2alpha-P, facilitated ribosome bypass of upstream ORFs, allowing for increased translation of the EPRS coding region. The 5'-leader of the EPRS mRNA directs preferential translation. Although a portion of the ribosomes that translate uORF2 can reinitiate downstream, scanning ribosomes also bypass uORF2 because of its noncanonical UUG1 initiation codon and initiate translation at the downstream coding sequence. UUG1 and CUG2 are overall repressing elements in EPRS translation control. Model for EPRS translation control, overview
physiological function
the multi-tRNA synthetase complex (MSC) component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at a Ser induces its dissociation from the MSC, after which it is guided to the antiviral signaling pathway, where it interacts with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. EPRS protects MAVS from PCBP2-mediated ubiquitination. The stimulus-inducible activation of MAVS by enzyme EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection. Phosphorylation of EPRS at a Ser is the driving force that leads to the antiviral roles of EPRS in regulating MAVS
physiological function
the multi-tRNA synthetase complex (MSC) component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induces its dissociation from the MSC, after which it is guided to the antiviral signaling pathway, where it interacts with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. EPRS protects MAVS from PCBP2-mediated ubiquitination. The stimulus-inducible activation of MAVS by enzyme EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection. Phosphorylation of EPRS at Ser990 is the driving force that leads to the antiviral roles of EPRS in regulating MAVS
additional information
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targets for oxidation-based inhibition are cysteines from a SWIM zinc-binding motif located in the tRNA acceptor helix-binding domain. Oxidation of the metal-binding site cysteine of GluRS1 significantly impaired catalysis. Also, binding of ATP or tRNA protects the distant cysteines of the SWIM motif
additional information
analysis of the contributions to aminoacylation efficiency made by the N-terminal Arc1p domain of Saccharomyces cerevisiae GluRS. tRNA recognition determinants in the acceptor arm, at the 3'-anticodon position and in the globular core, overview, overview
additional information
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analysis of the contributions to aminoacylation efficiency made by the N-terminal Arc1p domain of Saccharomyces cerevisiae GluRS. tRNA recognition determinants in the acceptor arm, at the 3'-anticodon position and in the globular core, overview, overview
additional information
homology structure modeling using structures of GluRSs identified from Burkholderia thailandensis and Thermosynechococcus elongatus, Uniprot IDs Q2SX36 and Q8DLI5, respectively, as search template, molecular docking
additional information
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homology structure modeling using structures of GluRSs identified from Burkholderia thailandensis and Thermosynechococcus elongatus, Uniprot IDs Q2SX36 and Q8DLI5, respectively, as search template, molecular docking
additional information
the enzyme is part of a multi-tRNA synthetase complex (MSC)
additional information
the enzyme is part of a multi-tRNA synthetase complex (MSC)
additional information
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analysis of the contributions to aminoacylation efficiency made by the N-terminal Arc1p domain of Saccharomyces cerevisiae GluRS. tRNA recognition determinants in the acceptor arm, at the 3'-anticodon position and in the globular core, overview, overview
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