TyrRS (CG4561, Aats-tyr) is the cytoplasmic tyrosyl-tRNA synthetase of Drosophila melanogaster, a class-I aminoacyl-tRNA synthetase of 525 residues and the fly ortholog of human YARS1 (68% identity; both in PANTHER subfamily PTHR11586:SF43). It activates L-tyrosine with ATP to form tyrosyl-adenylate and transfers the tyrosyl group to cytoplasmic tRNA(Tyr), supplying Tyr-tRNA(Tyr) for cytoplasmic protein synthesis; mitochondrial tRNA(Tyr) is charged by the separate TyrRS-m enzyme. The protein has an N-terminal Rossmann-fold catalytic domain with the class-I HIGH and KMSSS signatures, an anticodon-recognition region, and a C-terminal EMAP-II-like tRNA-binding domain. Outside translation, apoptotic loser cells in imaginal discs undergoing cell competition actively secrete TyrRS through a JNK- and Kish-dependent route; extracellular matrix metalloproteinase cleavage yields MiniTyr and EMAP fragments, and EMAP acts as a chemoattractant that activates PI3K in haemocytes and guides them to the dying cells. Cultured S2 cells also release TyrRS after serum deprivation. Fly TyrRS has been used to model YARS1-associated dominant-intermediate Charcot-Marie-Tooth neuropathy, where disease variants act through a gain of function rather than loss of aminoacylation.
Summary: TyrRS binds its tRNA(Tyr) substrate during aminoacylation and carries a C-terminal EMAP-II-like tRNA-binding domain (PF01588/IPR002547).
Reason: Binding of cognate tRNA is an intrinsic part of the tyrosine-tRNA ligase reaction, and the protein additionally has a recognised C-terminal tRNA-binding domain (PROSITE PS50886, residues 363-466). This is the informative nucleic-acid binding term for this enzyme; it is a component of the core aminoacylation activity rather than a separate function.
Summary: The nucleotide bound is ATP, the co-substrate used to form tyrosyl-adenylate.
Reason: Correct but general. The class-I catalytic domain (IPR002305) binds ATP for amino-acid activation; the gene already carries the more specific GO:0005524 ATP binding from the same InterPro mapping, which is the appropriate refinement.
Summary: The RNA bound is tRNA; the specific term tRNA binding is already present on this gene.
Reason: Correct but general. The substrate RNA of the enzyme is tRNA(Tyr), and the C-terminal domain is a tRNA-binding domain, so GO:0000049 tRNA binding (already annotated) is the appropriate refinement.
Summary: The amino-acid specificity is tyrosine, so tyrosine-tRNA ligase activity is the appropriate term.
Reason: Correct but general. Fly TyrRS is the cytoplasmic tyrosyl-tRNA synthetase (aaRS catalogue, PMID:26761199), is assayed for tyrosine-dependent aminoacylation (PMID:19561293, IDA), and carries GO:0004831 from IDA, TAS, IBA and IEA. Replace with that descendant.
the gene symbol for the cytoplasmic tyrosyl-tRNA synthetase is ‘TyrRS’, while ‘TyrRS-m’ is the designation for the gene encoding the mitochondrial tyrosyl-tRNA synthetase
Summary: PAINT placement of tyrosine-tRNA ligase activity at PTN000236303, with fly TyrRS (FBgn0027080) and human YARS1 (P54577) as experimental descendants, is sound.
Reason: Fly TyrRS and human YARS1 are both members of PANTHER subfamily PTHR11586:SF43 (cytoplasmic tyrosine-tRNA ligase), share 68% identity over their full length and retain the class-I catalytic signatures. The fly gene's own IDA annotation is among the descendant evidence used to place the node, which marks experimental grounding on the target itself. PAINT propagated only the ligase activity from this node, not the human nuclear, cytokine or starvation-response annotations; that selectivity is respected here.
Supporting Evidence:
file:DROME/TyrRS/TyrRS-bioinformatics/RESULTS.md
Both proteins are members of PANTHER subfamily PTHR11586:SF43 (TYROSINE--TRNA LIGASE, CYTOPLASMIC)
IDA PMID:19561293 Dominant mutations in the tyrosyl-tRNA synthetase gene recap...
ACCEPT
Summary: Core catalytic activity; FlyBase curators recorded direct assay evidence from the Drosophila DI-CMTC model study.
Reason: The cached record is abstract-only, but the abstract reports biochemical assays of TyrRS enzymatic activity across wild-type and disease variants, and the curators read the full text. The activity is also the conserved function of the SF43 subfamily. Accept and defer to the curator.
the gene symbol for the cytoplasmic tyrosyl-tRNA synthetase is ‘TyrRS’, while ‘TyrRS-m’ is the designation for the gene encoding the mitochondrial tyrosyl-tRNA synthetase
Summary: ATP is the co-substrate bound by the class-I catalytic domain to activate tyrosine.
Reason: The HIGH and KMSSS class-I signatures that contact ATP are conserved in the fly protein. ATP binding is a component of the core ligase activity and is as specific as warranted.
Supporting Evidence:
file:DROME/TyrRS/TyrRS-bioinformatics/RESULTS.md
KMSSS (class I signature): human KMSSS at 222-226; fly KMSSS at 221
Summary: Nuclear localization is shown for the human SF43 ortholog under stress, but not for native fly TyrRS; the UniProt location line rests on an ARBA rule.
Reason: Human YARS1, in the same PANTHER subfamily, translocates to the nucleus on serum starvation, heat shock or ER stress (PMID:25533949), and the lysine-rich segment that lies in the human nuclear-entry region is conserved in the fly protein. However, no study has localized endogenous fly TyrRS to the nucleus (fly CMT-model nuclear data use transgenic human YARS1), PAINT did not propagate the human nuclear annotations from PTN000236303, and the UniProt subcellular-location statement is ARBA-derived. The evidence neither establishes nor refutes a nuclear pool of the fly protein.
Summary: TyrRS is the cytoplasmic (not mitochondrial) tyrosyl-tRNA synthetase and acts in the cytoplasm.
Reason: Although the UniProt location line is ARBA-derived, cytoplasmic residence is independently established by the fly aaRS catalogue, which assigns CG4561 as the cytoplasmic enzyme and TyrRS-m as the mitochondrial one.
the gene symbol for the cytoplasmic tyrosyl-tRNA synthetase is ‘TyrRS’, while ‘TyrRS-m’ is the designation for the gene encoding the mitochondrial tyrosyl-tRNA synthetase
the gene symbol for the cytoplasmic tyrosyl-tRNA synthetase is ‘TyrRS’, while ‘TyrRS-m’ is the designation for the gene encoding the mitochondrial tyrosyl-tRNA synthetase
GO:0006418 tRNA aminoacylation for protein translation
IEA GO_REF:0000002
ACCEPT
Summary: TyrRS directly performs the tyrosyl-tRNA charging step that feeds cytoplasmic translation.
Reason: Core process. With GO:0006437 obsolete, this is the process term that pairs with GO:0004831.
Summary: GO:0006437 is obsolete because it restates GO:0004831; the process is captured by GO:0006418.
Reason: The biology is correct but the term is obsolete. Use GO:0006418 tRNA aminoacylation for protein translation for the process, with tyrosine specificity carried by GO:0004831.
The reason for obsoletion is that this term restates an existing molecular function, GO:0004831 tyrosine-tRNA ligase activity, and adds nothing beyond it.
The reason for obsoletion is that this term restates an existing molecular function, GO:0004831 tyrosine-tRNA ligase activity, and adds nothing beyond it.
Summary: ARBA-derived stress-response term; for native fly TyrRS the stress-associated evidence is that the protein is released, not that it performs a step of a stress response.
Reason: The ARBA rule reflects the vertebrate stress-induced nuclear TyrRS-PARP1 mechanism (PMID:25533949), which PAINT did not propagate from the SF43 node and which has not been tested for the fly protein. In flies, TyrRS is secreted by apoptotic loser cells and by serum-deprived S2 cells (PMID:26658841); in those settings TyrRS is the secreted cargo whose extracellular fragment then signals to haemocytes, which is captured by the chemoattractant and extracellular-region annotations. Being released under a stress condition does not show that TyrRS does any of the work of a cellular stress response, so neither this term nor its descendant response to starvation is proposed for the fly gene.
Supporting Evidence:
file:DROME/TyrRS/TyrRS-ncomms10022.txt
presence of secreted TyrRS-HA in the supernatant 24 h after serum deprivation
IDA PMID:26658841 Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA sy...
NEW
Summary: Endogenous TyrRS is detected outside loser cells in wing discs and in larval haemolymph during cell competition.
Reason: Direct fly evidence (endogenous TyrRS extracellular staining and haemolymph immunoblots, with Kish- and JNK-dependence) establishes a regulated extracellular pool in addition to the cytoplasmic enzyme. This location is conditional, not the steady-state site of the core activity.
IDA PMID:26658841 Active JNK-dependent secretion of Drosophila Tyrosyl-tRNA sy...
NEW
Summary: Secreted TyrRS, after MMP cleavage, releases an EMAP fragment that attracts haemocytes and activates PI3K in them.
Reason: The fly paper shows that secreted TyrRS and its EMAP fragment attract haemocytes in larvae and trigger a PI3K-activity reporter in them; TyrRS itself supplies the signalling moiety, so this is the product doing the work rather than serving as cargo. The haemocyte receptor is unknown. The activity is a conditional, non-core function of the processed extracellular protein and is supported by fly-specific evidence, not by transfer from the human cytokine data.
the gene symbol for the cytoplasmic tyrosyl-tRNA synthetase is ‘TyrRS’, while ‘TyrRS-m’ is the designation for the gene encoding the mitochondrial tyrosyl-tRNA synthetase
biochemical and genetic complementation experiments revealed that loss of enzymatic activity is not a common feature of DI-CMTC-associated mutations
file:DROME/TyrRS/TyrRS-bioinformatics/RESULTS.md
Both proteins are members of PANTHER subfamily PTHR11586:SF43 (TYROSINE--TRNA LIGASE, CYTOPLASMIC)
During cell competition, TyrRS secreted from apoptotic loser cells is cleaved by matrix metalloproteinases, and its EMAP fragment acts as an extracellular chemoattractant that recruits haemocytes.
Q: Does endogenous fly TyrRS enter the nucleus under stress, as human YARS1 does, given that the lysine-rich segment of the human nuclear-entry region is conserved?
Q: What haemocyte receptor mediates the response to the EMAP fragment of secreted fly TyrRS?
Suggested Experiments
Experiment: Endogenously tag TyrRS by CRISPR knock-in and image its distribution in imaginal discs and fat body under heat shock, ER stress and nutrient deprivation, to test for a nuclear pool of the native protein.
Experiment: Express a non-cleavable TyrRS variant in loser cells to test whether MMP processing is required for haemocyte recruitment.
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Fly TyrRS has established aminoacylation and regulated extracellular functions. Its release from serum-deprived S2 cells shows TyrRS as secreted cargo of a starvation-exposed cell, not a participant doing the work of a starvation response, and the vertebrate nuclear starvation mechanism is untested in flies, so the response-to-starvation prediction is unresolved. The specific resveratrol-binding GO term is obsolete and direct fly binding is unmeasured.
Review rationale: The fly study detects TyrRS-HA in S2-cell supernatant after serum deprivation, with membrane-integrity and tubulin controls excluding release by cell lysis. That shows TyrRS is released by a starvation-exposed cell, but TyrRS is the secreted cargo there; release does not show that the protein performs a step of a starvation response, and the gene review marks the broader ARBA-derived response-to-stress annotation as over-annotated on the same grounds. The participatory mechanism that would justify the term, starvation-induced nuclear translocation of YARS1 and PARP1 activation, is documented for the vertebrate SF43 ortholog but was not propagated by PAINT and has not been tested for fly TyrRS. No fly study links TyrRS to a starvation response (PubMed search of Drosophila TyrRS with starvation or nutrient terms returned no records). Available evidence neither validates nor refutes the prediction.
Review rationale: The exact predicted term, GO:1905594 resveratrol binding, is obsolete, replacement-less and explicitly out of scope for evolved molecular functions. OpenScientist found the fly tyrosine active-site pocket conserved with the human YARS1 pocket that binds resveratrol, so in-vitro binding by fly Q9VV60 remains plausible by homology but unmeasured. The biological prediction therefore cannot be validated or refuted with available evidence, and the obsolete xenobiotic-specific GO term should not be curated even if an in-vitro fly-binding assay is eventually positive.
Supporting Evidence:
file:DROME/TyrRS/TyrRS-hypotheses/fly41-resveratrol-recognition/openscientist.md: "Fly TyrRS almost certainly *can* accommodate resveratrol in its conserved tyrosine pocket (68.4% identity to human, all nine contact residues identical), but this has never been measured in *Drosophila*, represents a xenobiotic pharmacological interaction rather than an evolved function"