YARS1 encodes cytoplasmic tyrosyl-tRNA synthetase (TyrRS), a class I aminoacyl-tRNA synthetase that attaches L-tyrosine to tRNA(Tyr) in two steps: ATP-dependent formation of tyrosyl-adenylate in the Rossmann-fold catalytic domain, then transfer to the tRNA acceptor end. The 528-residue protein is a homodimer made of a catalytic domain, an anticodon-recognition domain, and a vertebrate-appended C-terminal EMAP-II-like tRNA-binding domain. It acts mainly in the cytosol and supplies Tyr-tRNA(Tyr) for cytoplasmic translation. A regulated fraction enters the nucleus through a hexapeptide NLS in the anticodon-recognition domain that is masked when tRNA(Tyr) is bound. Nuclear TyrRS binds PARP1 and stimulates its auto-poly-ADP-ribosylation, which serum starvation and resveratrol enhance; resveratrol occupies the tyrosine pocket and inhibits aminoacylation. Under apoptotic conditions full-length TyrRS is secreted, and elastase cleavage releases mini-TyrRS, an IL-8-like cytokine that binds CXCR1, and a chemotactic EMAP-II-like C-terminal fragment. Heterozygous YARS1 variants cause dominant intermediate Charcot-Marie-Tooth neuropathy type C. Biallelic hypomorphic variants cause an infantile-onset multisystem disease.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000049 tRNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: tRNA binding inferred from the InterPro tRNA-binding (EMAP-II-like) domain; human TyrRS binds tRNA(Tyr) through its anticodon-recognition domain and the C-terminal domain is proposed to direct tRNA to the active site. Reason: Binding of cognate tRNA(Tyr) is an intrinsic part of the aminoacylation mechanism and is supported experimentally by the NLS/tRNA(Tyr) interaction data (PMID:22291016). The IEA mapping is appropriate. Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt IPR002547; tRNA-bd_dom PMID:22291016 this nuclear localization signal (NLS) sequence motif is also important for interacting with tRNA(Tyr) |
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | TOO GENERAL | Summary: Generic nucleotide binding inferred from class-I synthetase signatures. Reason: True (ATP is a substrate) but uninformative; GO:0005524 ATP binding, accepted in this review, already entails it. Supporting Evidence: PMID:9162081 an amino-terminal Rossmann fold domain that is responsible for formation of the activated E.Tyr-AMP intermediate |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | TOO GENERAL | Summary: YARS1 was recovered in HeLa mRNA interactome capture. Reason: RNA binding is true (YARS1 binds tRNA), but the more specific GO:0000049 tRNA binding, accepted in this review, already entails it. The interactome-capture result does not establish a specific mRNA-binding function. Supporting Evidence: PMID:22658674 We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria |
| GO:0004812 aminoacyl-tRNA ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic aminoacyl-tRNA ligase activity from the class-I synthetase InterPro signature. Reason: Correct but general. The specific activity, tyrosine-tRNA ligase, is experimentally established and already carried by this gene (IDA, IBA). Proposed replacements: tyrosine-tRNA ligase activity Supporting Evidence: PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr file:human/YARS1/YARS1-uniprot.txt IPR002307; Tyr-tRNA-ligase |
| GO:0004831 tyrosine-tRNA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic activity. Human cytoplasmic TyrRS charges human tRNA(Tyr) with tyrosine via a Tyr-AMP intermediate; this is directly measured for the recombinant human enzyme (PMID:9162081), is inhibited by resveratrol (PMID:25533949), and is reduced by disease and NLS mutations (PMID:16429158, PMID:22291016). Reason: Tyrosine-tRNA ligase activity is the defining, experimentally established function of YARS1. The IBA comes from PAINT node PTN000236303 within PANTHER subfamily PTHR11586:SF43 (cytoplasmic TyrRS); YARS1 appears among its own sources because it carries direct experimental evidence, which is expected, not circular. Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt PTHR11586:SF43; TYROSINE--TRNA LIGASE, CYTOPLASMIC PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr |
| GO:0004831 tyrosine-tRNA ligase activity | IDA PMID:22291016 tRNA-controlled nuclear import of a human tRNA synthetase. | ACCEPT | Summary: Core catalytic activity. Human cytoplasmic TyrRS charges human tRNA(Tyr) with tyrosine via a Tyr-AMP intermediate; this is directly measured for the recombinant human enzyme (PMID:9162081), is inhibited by resveratrol (PMID:25533949), and is reduced by disease and NLS mutations (PMID:16429158, PMID:22291016). Reason: Tyrosine-tRNA ligase activity is the defining, experimentally established function of YARS1. Supporting Evidence: PMID:22291016 mutational alteration of the hexapeptide simultaneously attenuated aminoacylation and nuclear localization |
| GO:0004831 tyrosine-tRNA ligase activity | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | ACCEPT | Summary: Core catalytic activity. Human cytoplasmic TyrRS charges human tRNA(Tyr) with tyrosine via a Tyr-AMP intermediate; this is directly measured for the recombinant human enzyme (PMID:9162081), is inhibited by resveratrol (PMID:25533949), and is reduced by disease and NLS mutations (PMID:16429158, PMID:22291016). Reason: Tyrosine-tRNA ligase activity is the defining, experimentally established function of YARS1. Supporting Evidence: PMID:25533949 We found RSV strongly inhibited TyrRS with a Ki-value of 22 ΞΌM |
| GO:0004831 tyrosine-tRNA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core catalytic activity. Human cytoplasmic TyrRS charges human tRNA(Tyr) with tyrosine via a Tyr-AMP intermediate; this is directly measured for the recombinant human enzyme (PMID:9162081), is inhibited by resveratrol (PMID:25533949), and is reduced by disease and NLS mutations (PMID:16429158, PMID:22291016). Reason: Tyrosine-tRNA ligase activity is the defining, experimentally established function of YARS1. The IEA (EC 6.1.1.1/RHEA:10220/IPR002307) agrees with the experimental data. Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt IPR002307; Tyr-tRNA-ligase PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr |
| GO:0004831 tyrosine-tRNA ligase activity | TAS PMID:9162081 Human tyrosyl-tRNA synthetase shares amino acid sequence hom... | ACCEPT | Summary: Core catalytic activity. Human cytoplasmic TyrRS charges human tRNA(Tyr) with tyrosine via a Tyr-AMP intermediate; this is directly measured for the recombinant human enzyme (PMID:9162081), is inhibited by resveratrol (PMID:25533949), and is reduced by disease and NLS mutations (PMID:16429158, PMID:22291016). Reason: Tyrosine-tRNA ligase activity is the defining, experimentally established function of YARS1. PMID:9162081 reports kinetic analysis of the recombinant human enzyme. Supporting Evidence: PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr |
| GO:0005153 interleukin-8 receptor binding | TAS PMID:10102815 Two distinct cytokines released from a human aminoacyl-tRNA ... | KEEP AS NON CORE | Summary: The N-terminal catalytic fragment (mini-TyrRS), released from secreted TyrRS by leukocyte elastase, binds the interleukin-8 type A receptor (CXCR1) and acts as an IL-8-like cytokine. Reason: Supported by direct experiments on human mini-TyrRS (PMID:10102815), and the cytokine activity depends on the ELR motif (PMID:12427973). It is a property of a proteolytic fragment, not of the full-length enzyme, which lacks cytokine activity, so it is a non-core moonlighting function. Supporting Evidence: PMID:10102815 The catalytic amino-terminal domain binds to the interleukin-8 type A receptor and functions as an interleukin-8-like cytokine. PMID:12427973 The full-length native TyrRS lacks cytokine activity. |
| GO:0005515 protein binding | IPI PMID:24965446 Host factors that interact with the pestivirus N-terminal pr... | REMOVE | Summary: YARS1 was co-purified with the pestivirus N-terminal protease Npro in a host-factor proteomic screen. Reason: Generic protein binding with a viral protein from a proteomic screen; it does not establish an informative function for YARS1. Removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | MODIFY | Summary: YARS1 binds the C-terminal domain of PARP1 and stimulates its NAD+-dependent auto-poly-ADP-ribosylation, both in vitro and in cells. Reason: The paper shows a functional consequence of the interaction: TyrRS activates PARP1 in a concentration-dependent manner in vitro, and resveratrol enhances this. GO:0008047 enzyme activator activity is the informative replacement for generic protein binding. Proposed replacements: enzyme activator activity Supporting Evidence: PMID:25533949 TyrRS interacted specifically with the C-domain of PARP-1 PMID:25533949 In the absence of RSV, concentration-dependent activation of PARP-1 by TyrRS was observed in vitro |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:O75925 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:P17024 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:P37235 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q14781-2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q5M9N0-2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q6P1M0-2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q86SG2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q86V28 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q8IYM2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q8IYN2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q8N7B6-2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q8NHQ1-3 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q8WXF7 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q96DX5-3 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q99932-2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q9H3K2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q9UBF1 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Binary interaction with UniProtKB:Q9UNS2 from a large-scale interactome map of neurodegenerative-disease proteins. Reason: Generic protein binding is uninformative. This interaction comes from a high-throughput screen and does not establish a functional activity for YARS1; removal does not mean the interaction is false. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding inferred from the class-I aminoacyl-tRNA synthetase catalytic domain. Reason: ATP is a substrate of the tyrosine activation step; the Rossmann-fold catalytic domain forms the Tyr-AMP intermediate (PMID:9162081). The IEA is consistent with the established catalytic mechanism. Supporting Evidence: PMID:9162081 an amino-terminal Rossmann fold domain that is responsible for formation of the activated E.Tyr-AMP intermediate |
| GO:0005576 extracellular region | TAS PMID:10102815 Two distinct cytokines released from a human aminoacyl-tRNA ... | KEEP AS NON CORE | Summary: Full-length TyrRS is secreted from cells under apoptotic conditions. Reason: Secretion under apoptotic conditions is reported for human TyrRS (PMID:10102815); the extracellular pool is minor and condition-specific relative to the cytosolic enzyme. Supporting Evidence: PMID:10102815 Under apoptotic conditions in cell culture, the full-length enzyme is secreted, and the two cytokine activities can be generated by leukocyte elastase, an extracellular protease. |
| GO:0005634 nucleus | IDA PMID:22291016 tRNA-controlled nuclear import of a human tRNA synthetase. | ACCEPT | Summary: A regulated fraction of YARS1 enters the nucleus through an NLS in the anticodon-recognition domain; import is suppressed by tRNA(Tyr) binding and increased by serum starvation or resveratrol. Reason: Nuclear localization is directly demonstrated in human cells (PMID:22291016, PMID:25533949), and the nucleus is where TyrRS performs its experimentally established PARP1-activating function. The pool is conditional and regulated by tRNA(Tyr) binding, while the bulk of the protein and the aminoacylation function are cytosolic. Supporting Evidence: PMID:22291016 human tyrosyl-tRNA synthetase (TyrRS) distributes to the nucleus and that the nuclear import of human TyrRS is regulated by its cognate tRNA(Tyr) |
| GO:0005634 nucleus | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | ACCEPT | Summary: A regulated fraction of YARS1 enters the nucleus through an NLS in the anticodon-recognition domain; import is suppressed by tRNA(Tyr) binding and increased by serum starvation or resveratrol. Reason: Nuclear localization is directly demonstrated in human cells (PMID:22291016, PMID:25533949), and the nucleus is where TyrRS performs its experimentally established PARP1-activating function. The pool is conditional and regulated by tRNA(Tyr) binding, while the bulk of the protein and the aminoacylation function are cytosolic. Supporting Evidence: PMID:25533949 Thus, both serum starvation and RSV promoted nuclear translocation of TyrRS |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: A regulated fraction of YARS1 enters the nucleus through an NLS in the anticodon-recognition domain; import is suppressed by tRNA(Tyr) binding and increased by serum starvation or resveratrol. Reason: Nuclear localization is directly demonstrated in human cells (PMID:22291016, PMID:25533949), and the nucleus is where TyrRS performs its experimentally established PARP1-activating function. The pool is conditional and regulated by tRNA(Tyr) binding, while the bulk of the protein and the aminoacylation function are cytosolic. Supporting Evidence: PMID:22291016 human tyrosyl-tRNA synthetase (TyrRS) distributes to the nucleus and that the nuclear import of human TyrRS is regulated by its cognate tRNA(Tyr) PMID:25533949 Thus, both serum starvation and RSV promoted nuclear translocation of TyrRS |
| GO:0005737 cytoplasm | EXP PMID:30304524 Homozygosity for a mutation affecting the catalytic domain o... | MODIFY | Summary: YARS1 is a soluble cytoplasmic enzyme in resting cells; the cytoplasmic pool is the cytosolic translation-supporting pool. Reason: Correct but general: the evidence (immunofluorescence, fractionation, and the soluble aminoacylation function) places the protein in the cytosol, which this gene already carries (HPA IDA, PMID:22291016 IDA, Reactome TAS). Refine to GO:0005829 cytosol. Proposed replacements: cytosol Supporting Evidence: PMID:30304524 Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. |
| GO:0005737 cytoplasm | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | MODIFY | Summary: YARS1 is a soluble cytoplasmic enzyme in resting cells; the cytoplasmic pool is the cytosolic translation-supporting pool. Reason: Correct but general: the evidence (immunofluorescence, fractionation, and the soluble aminoacylation function) places the protein in the cytosol, which this gene already carries (HPA IDA, PMID:22291016 IDA, Reactome TAS). Refine to GO:0005829 cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt Note=Cytoplasmic in normal conditions (PubMed:25533949). |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: YARS1 is a soluble cytoplasmic enzyme in resting cells; the cytoplasmic pool is the cytosolic translation-supporting pool. Reason: Correct but general: the evidence (immunofluorescence, fractionation, and the soluble aminoacylation function) places the protein in the cytosol, which this gene already carries (HPA IDA, PMID:22291016 IDA, Reactome TAS). Refine to GO:0005829 cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt Note=Cytoplasmic in normal conditions (PubMed:25533949). |
| GO:0005737 cytoplasm | TAS PMID:9162081 Human tyrosyl-tRNA synthetase shares amino acid sequence hom... | MODIFY | Summary: YARS1 is a soluble cytoplasmic enzyme in resting cells; the cytoplasmic pool is the cytosolic translation-supporting pool. Reason: Correct but general: the evidence (immunofluorescence, fractionation, and the soluble aminoacylation function) places the protein in the cytosol, which this gene already carries (HPA IDA, PMID:22291016 IDA, Reactome TAS). Refine to GO:0005829 cytosol. Proposed replacements: cytosol Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt Note=Cytoplasmic in normal conditions (PubMed:25533949). |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: YARS1 is a cytosolic enzyme that charges tRNA(Tyr) for cytoplasmic translation. Reason: The cytosol is the site of the core aminoacylation function; consistent with the HPA, primary-literature and Reactome sources. Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt Note=Cytoplasmic in normal conditions (PubMed:25533949). |
| GO:0005829 cytosol | IDA PMID:22291016 tRNA-controlled nuclear import of a human tRNA synthetase. | ACCEPT | Summary: YARS1 is a cytosolic enzyme that charges tRNA(Tyr) for cytoplasmic translation. Reason: The cytosol is the site of the core aminoacylation function; consistent with the HPA, primary-literature and Reactome sources. Supporting Evidence: PMID:22291016 human tyrosyl-tRNA synthetase (TyrRS) distributes to the nucleus and that the nuclear import of human TyrRS is regulated by its cognate tRNA(Tyr) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-379980 | ACCEPT | Summary: YARS1 is a cytosolic enzyme that charges tRNA(Tyr) for cytoplasmic translation. Reason: The cytosol is the site of the core aminoacylation function; consistent with the HPA, primary-literature and Reactome sources. Supporting Evidence: Reactome:R-HSA-379980 YARS (cytosolic tyrosyl tRNA synthetase) catalyzes the reaction of tyrosine, tRNA(Tyr), and ATP to form Tyr tRNA(Tyr), AMP, and pyrophosphate. |
| GO:0006418 tRNA aminoacylation for protein translation | IEA GO_REF:0000002 | ACCEPT | Summary: YARS1 charges tRNA(Tyr) for cytoplasmic protein synthesis. Reason: Core biological process, directly performed by YARS1 through its tyrosine-tRNA ligase activity. Supporting Evidence: PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr Reactome:R-HSA-379980 YARS (cytosolic tyrosyl tRNA synthetase) catalyzes the reaction of tyrosine, tRNA(Tyr), and ATP to form Tyr tRNA(Tyr), AMP, and pyrophosphate. |
| GO:0006437 obsolete tyrosyl-tRNA aminoacylation | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | MODIFY | Summary: Tyrosyl-tRNA aminoacylation by YARS1; the process is real and core. Reason: GO:0006437 is obsolete (QuickGO: replaced_by GO:0006418) because it restated GO:0004831. The biology is correct; the replacement process term is GO:0006418 tRNA aminoacylation for protein translation, which this gene already carries. Proposed replacements: tRNA aminoacylation for protein translation Supporting Evidence: PMID:25533949 We found RSV strongly inhibited TyrRS with a Ki-value of 22 ΞΌM |
| GO:0006437 obsolete tyrosyl-tRNA aminoacylation | IEA GO_REF:0000002 | MODIFY | Summary: Tyrosyl-tRNA aminoacylation by YARS1; the process is real and core. Reason: GO:0006437 is obsolete (QuickGO: replaced_by GO:0006418) because it restated GO:0004831. The biology is correct; the replacement process term is GO:0006418 tRNA aminoacylation for protein translation, which this gene already carries. Proposed replacements: tRNA aminoacylation for protein translation Supporting Evidence: file:human/YARS1/YARS1-uniprot.txt IPR002307; Tyr-tRNA-ligase |
| GO:0006437 obsolete tyrosyl-tRNA aminoacylation | TAS PMID:9162081 Human tyrosyl-tRNA synthetase shares amino acid sequence hom... | MODIFY | Summary: Tyrosyl-tRNA aminoacylation by YARS1; the process is real and core. Reason: GO:0006437 is obsolete (QuickGO: replaced_by GO:0006418) because it restated GO:0004831. The biology is correct; the replacement process term is GO:0006418 tRNA aminoacylation for protein translation, which this gene already carries. Proposed replacements: tRNA aminoacylation for protein translation Supporting Evidence: PMID:9162081 human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNATyr |
| GO:0006915 apoptotic process | TAS PMID:10102815 Two distinct cytokines released from a human aminoacyl-tRNA ... | MARK AS OVER ANNOTATED | Summary: Annotation derived from the observation that TyrRS is secreted from apoptotic cells. Reason: The source paper shows that TyrRS is released under apoptotic conditions and that its fragments act as cytokines; it only speculates that secretion may contribute to apoptosis. There is no evidence that YARS1 executes a step of the apoptotic program; it is secreted as a consequence of it. Supporting Evidence: PMID:10102815 Secretion of this tRNA synthetase may contribute to apoptosis both by arresting translation and producing needed cytokines. PMID:10102815 Under apoptotic conditions in cell culture, the full-length enzyme is secreted, and the two cytokine activities can be generated by leukocyte elastase, an extracellular protease. |
| GO:0006950 response to stress | IEA GO_REF:0000117 | TOO GENERAL | Summary: Response to stress assigned by an ARBA machine-learning rule. Reason: YARS1 relocates to the nucleus and activates PARP1 under serum starvation (PMID:25533949), so a stress-response role is plausible, but GO:0042594 response to starvation, kept in this review on experimental evidence, already entails it. Supporting Evidence: PMID:25533949 Thus, both serum starvation and RSV promoted nuclear translocation of TyrRS |
| GO:0016604 nuclear body | IDA GO_REF:0000052 | UNDECIDED | Summary: Nuclear body localization from Human Protein Atlas immunofluorescence. Reason: The nuclear pool of YARS1 is well supported, but no primary study reports a specific nuclear-body substructure, and the HPA antibody image cannot be checked here. |
| GO:0036094 small molecule binding | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | MODIFY | Summary: Resveratrol binds the tyrosine pocket of the TyrRS active site (2.1 A co-crystal), and L-tyrosine binds the same site. Reason: Correct but general. The physiological small molecule bound in this pocket is the substrate L-tyrosine, co-crystallized in the same study and in PMID:14671330. Resveratrol binding is a pharmacological interaction with no specific GO term; L-tyrosine binding is the informative replacement. Proposed replacements: L-tyrosine binding Supporting Evidence: PMID:25533949 Here we present a 2.1 Γ
co-crystal structure of resveratrol bound to the active site of TyrRS. PMID:25533949 Crystallization of Hs mini-TyrRS with RSV and, separately, with tyrosine yielded co-crystal structures PMID:14671330 A cocrystal structure of an active fragment of human tyrosyl-tRNA synthetase with its cognate amino acid analog was also solved at 1.6 A. |
| GO:0042594 response to starvation | IDA PMID:25533949 A human tRNA synthetase is a potent PARP1-activating effecto... | KEEP AS NON CORE | Summary: Under serum starvation human TyrRS translocates to the nucleus, associates with PARP1 and enhances PARP1 auto-poly-ADP-ribosylation. Reason: YARS1 acts as an effector in the cellular starvation response by stimulating PARP1 (PMID:25533949). This is a non-canonical, condition-specific role, not the core translational function. Supporting Evidence: PMID:25533949 Thus, both serum starvation and RSV promoted nuclear translocation of TyrRS PMID:25533949 In the absence of RSV, concentration-dependent activation of PARP-1 by TyrRS was observed in vitro |
| GO:0042803 protein homodimerization activity | IDA PMID:30304524 Homozygosity for a mutation affecting the catalytic domain o... | NEW | Summary: Human YARS1 forms a homodimer; dimerization is required for catalysis, and the disease variant P167T at the dimer interface impairs dimerization in human cells. Reason: Homodimerization is shown for human YARS1 in crystal structures and in HEK cells, and disrupting it impairs function (PMID:30304524, PMID:12427973). No GOA annotation records the quaternary structure. Supporting Evidence: PMID:30304524 This variant lies within a highly conserved interface required for protein homodimerization, an essential step in YARS catalytic function. PMID:30304524 Recombinant YARS p.Pro167Thr demonstrated normal subcellular localization, but greatly diminished ability to homodimerize in human embryonic kidney cells. PMID:12427973 In the crystal structure, mini-TyrRS is a dimer |
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Download this section (compressed HTML)Q: Does endogenous YARS1 activate PARP1 under physiological stress without exogenous resveratrol, and which tyrosine-pocket ligands cause the conformational switch?
Q: Are the cytokine activities of mini-TyrRS and the EMAP-II-like fragment produced in vivo in humans, and in which tissues and conditions?
Q: Do CMT-associated YARS1 variants cause neuropathy through loss of aminoacylation, through a gain of non-canonical function, or both?
Experiment: Knock in an aminoacylation-competent but PARP1-binding-deficient YARS1 (for example, a C-domain/linker mutant) and measure PARylation and stress signalling during serum starvation, to separate the nuclear function from translation.
Experiment: Use mass spectrometry to detect endogenous mini-TyrRS and the C-terminal fragment in human plasma or inflammatory exudates, to test whether secreted cytokine forms arise in vivo.
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