TARS2 encodes the nuclear-encoded mitochondrial threonyl-tRNA synthetase, a homodimeric class II aminoacyl-tRNA synthetase imported into the mitochondrial matrix. It activates L-threonine with ATP and transfers it to mitochondrial tRNA(Thr), and its editing domain hydrolyses serine mischarged onto tRNA(Thr) (post-transfer proofreading). The resulting Thr-tRNA(Thr) is required for translation of the thirteen mtDNA-encoded oxidative phosphorylation subunits. Biallelic TARS2 variants reduce charged mitochondrial tRNA(Thr) and cause an early-onset mitochondrial encephalomyopathy with multiple respiratory-chain defects (COXPD21).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Nucleotide binding, from an InterPro-derived electronic inference. Reason: True of TARS2 but uninformative, because GO:0005524 ATP binding, kept in this review, already entails it and is the nucleotide actually used in the aminoacylation reaction. GO:0005524 is a confirmed descendant of GO:0000166. The informative activity, threonine-tRNA ligase, sits in a different branch and so is not a refinement target for this row. Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0002161 aminoacyl-tRNA deacylase activity | IDA PMID:26811336 A Human Disease-causing Point Mutation in Mitochondrial Thre... | ACCEPT | Summary: Aminoacyl-tRNA deacylase activity, from direct assay of the purified enzyme: human mitochondrial ThrRS misactivates serine and clears the mischarged product by post-transfer editing. Reason: Purified human mitochondrial ThrRS misactivates serine and clears mischarged products by post-transfer editing, i.e. it deacylates mischarged aminoacyl-tRNA. This proofreading activity is an intrinsic part of the TARS2 enzyme function. Supporting Evidence: PMID:26811336 hmtThrRS misactivates non-cognate Ser and uses post-transfer editing to clear erroneously synthesized products. PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0004812 aminoacyl-tRNA ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: Aminoacyl-tRNA ligase activity, the family-level parent of the threonine-specific term, from an electronic inference. Reason: Aminoacyl-tRNA ligase activity is correct but too general; the experimentally established activity is threonine-tRNA ligase activity (GO:0004829). Proposed replacements: threonine-tRNA ligase activity Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0004829 threonine-tRNA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Threonine-tRNA ligase activity is the core MF of TARS2; the IBA agrees with direct assays of purified human mitochondrial ThrRS. Reason: Threonine-tRNA ligase activity is the core MF of TARS2; the IBA agrees with direct assays of purified human mitochondrial ThrRS. Supporting Evidence: PMID:26811336 Herein, we cloned TARS2 and purified the wild-type and P282L mutant hmtThrRS. PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0004829 threonine-tRNA ligase activity | IDA PMID:26811336 A Human Disease-causing Point Mutation in Mitochondrial Thre... | ACCEPT | Summary: Direct in vitro assays of purified human mitochondrial ThrRS measured threonine activation and tRNA(Thr) aminoacylation, impaired by the disease variant P282L. Reason: Direct in vitro assays of purified human mitochondrial ThrRS measured threonine activation and tRNA(Thr) aminoacylation, impaired by the disease variant P282L. Core MF. Supporting Evidence: PMID:26811336 Herein, we cloned TARS2 and purified the wild-type and P282L mutant hmtThrRS. PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0004829 threonine-tRNA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined IEA agrees with experimental data; threonine-tRNA ligase activity is the core MF. Reason: The combined IEA agrees with experimental data; threonine-tRNA ligase activity is the core MF. Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. Reason: Protein binding from the HuRI binary yeast two-hybrid screen is uninformative about TARS2 function; removal does not imply the interactions are false. The reported partners (mostly membrane and secretory-pathway proteins) have no established connection to mitochondrial threonyl-tRNA charging, and the term itself should be avoided. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding, from an InterPro-derived electronic inference. Reason: ATP binding is part of the aminoacylation reaction (threonine is activated by ATP to Thr-AMP) and is not a separate function. Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0005737 cytoplasm | IEA GO_REF:0000002 | MODIFY | Summary: Cytoplasm is an InterPro-derived term inherited from the bacterial-type ThrRS family. Reason: Correct but less specific than the established location; cytoplasm is an InterPro-derived term inherited from the bacterial-type ThrRS family, and in GO it includes mitochondria. The gene already carries GO:0005759 mitochondrial matrix as an accepted row, and GO:0005759 is a confirmed descendant of GO:0005737. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:26811336 Mitochondria require all translational components, including aminoacyl-tRNA synthetases (aaRSs), to complete organelle protein synthesis. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MODIFY | Summary: Mitochondrion is supported by the MitoCoP high-confidence mitochondrial proteome and by the mitochondrial translation function of TARS2. Reason: Correct but less specific than the established location, and refined here for the same reason as the GO:0005737 cytoplasm row in this review. TARS2 acts in the mitochondrial matrix, the gene already carries GO:0005759 as an accepted row, and GO:0005759 is a confirmed descendant of GO:0005739. The MitoCoP high-confidence proteome and the mitochondrial translation function remain the support. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:34800366 We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP). PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Mitochondrial matrix is where mitochondrial tRNA aminoacylation occurs and matches the function of TARS2. Reason: Mitochondrial matrix is where mitochondrial tRNA aminoacylation occurs and matches the function of TARS2. Supporting Evidence: PMID:26811336 Mitochondria require all translational components, including aminoacyl-tRNA synthetases (aaRSs), to complete organelle protein synthesis. PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0006418 tRNA aminoacylation for protein translation | IEA GO_REF:0000002 | MODIFY | Summary: Involvement in tRNA aminoacylation for protein translation, with no compartment specified. Reason: tRNA aminoacylation for protein translation is correct but nonspecific; TARS2 charges mitochondrial tRNA(Thr) for mitochondrial translation (GO:0070127). Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0006435 obsolete threonyl-tRNA aminoacylation | IBA GO_REF:0000033 | MODIFY | Summary: Involvement in threonyl-tRNA aminoacylation, a term GO has since obsoleted. Reason: Threonyl-tRNA aminoacylation (now obsolete in GO) describes the TARS2 reaction; the appropriate current process term is tRNA aminoacylation for mitochondrial protein translation (GO:0070127). Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0006435 obsolete threonyl-tRNA aminoacylation | IEA GO_REF:0000120 | MODIFY | Summary: Involvement in threonyl-tRNA aminoacylation, a term GO has since obsoleted. Reason: Threonyl-tRNA aminoacylation (now obsolete in GO) describes the TARS2 reaction; the appropriate current process term is tRNA aminoacylation for mitochondrial protein translation (GO:0070127). Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:26811336 the mutation induces a decrease in Thr activation, aminoacylation, and proofreading activities |
| GO:0042803 protein homodimerization activity | IDA PMID:26811336 A Human Disease-causing Point Mutation in Mitochondrial Thre... | KEEP AS NON CORE | Summary: Human mitochondrial ThrRS is a homodimer and an exon-8/9-skipping splice variant that fails to dimerize is inactive, so dimerization is structurally required. Reason: Human mitochondrial ThrRS is a homodimer and an exon-8/9-skipping splice variant that fails to dimerize is inactive, so dimerization is structurally required. It is a structural property supporting the core catalytic function rather than a function in its own right. Supporting Evidence: PMID:26811336 In HEK293T cells, the variant does not dimerize and cannot complement the ThrRS knock-out strain in yeast |
| GO:0043039 tRNA charging | IEA GO_REF:0000002 | MODIFY | Summary: Involvement in tRNA charging, with neither the amino acid nor the compartment specified. Reason: tRNA charging is correct but not specific; TARS2 charges tRNA(Thr) for mitochondrial translation (GO:0070127). Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0070159 obsolete mitochondrial threonyl-tRNA aminoacylation | TAS PMID:15779907 Toward the full set of human mitochondrial aminoacyl-tRNA sy... | MODIFY | Summary: Involvement in mitochondrial threonyl-tRNA aminoacylation, a term GO has since obsoleted. Reason: Mitochondrial threonyl-tRNA aminoacylation (now obsolete in GO) is the correct biology for TARS2; replace with tRNA aminoacylation for mitochondrial protein translation (GO:0070127). Proposed replacements: tRNA aminoacylation for mitochondrial protein translation Supporting Evidence: PMID:15779907 Genes for the remaining missing synthetases were also found with the exception of glutaminyl-tRNA synthetase. PMID:24827421 Severe decrease in the aminoacylated tRNAThr was observed in P2 fibroblasts. |
| GO:0106074 aminoacyl-tRNA metabolism involved in translational fidelity | IEA GO_REF:0000108 | ACCEPT | Summary: Inferred from the deacylase MF, and correct: TARS2 proofreads mischarged Ser-tRNA(Thr). Reason: Inferred from the deacylase MF, and the inference holds - the purified enzyme clears Ser mischarged onto tRNA(Thr) by post-transfer editing, which is what this term names. Retained as core alongside the GO:0002161 core function below. Proofreading is in service of accurate aminoacylation, which is not the same as being part of it: the reaction is a distinct one on a distinct substrate, and without it serine would be incorporated into the mtDNA-encoded respiratory-chain subunits. Supporting Evidence: PMID:26811336 hmtThrRS misactivates non-cognate Ser and uses post-transfer editing to clear erroneously synthesized products. |
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Download this section (compressed HTML)Q: Does the non-canonical interaction of TARS2 with Rag GTPases reported for mTORC1 signalling occur at physiological TARS2 levels outside mitochondria, and does it contribute to disease phenotypes independently of tRNA(Thr) charging?
Q: Why does partial loss of TARS2 aminoacylation activity produce a predominantly neurological phenotype despite ubiquitous expression?
Experiment: Measure steady-state charging of mt-tRNA(Thr) and mitochondrial translation rates in iPSC-derived neurons and cardiomyocytes carrying patient TARS2 alleles, with and without rescue by catalytically dead versus editing-dead TARS2.
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