GARS1 encodes glycyl-tRNA synthetase, a homodimeric class II aminoacyl-tRNA synthetase that uses ATP to attach glycine to tRNA(Gly). Its activity supplies glycyl-tRNA for cytosolic and mitochondrial protein synthesis. Alternative translation initiation yields a 739-residue precursor and a 685-residue product lacking the N-terminal 54 residues; initiation and targeting mechanisms influence their compartmental distribution without establishing mutually exclusive pools. Human GlyRS also synthesizes diadenosine tetraphosphate from ATP in biochemical assays, although its contribution to physiological Ap4A homeostasis remains unresolved. Neuronal and axonal pools and extracellular release have been reported; dominant neuropathy-associated variants can gain abnormal interactions, whereas biallelic loss of charging capacity causes broader cellular dysfunction.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000166 nucleotide binding | IEA GO_REF:0000002 | MODIFY | Summary: ATP binding specifies the nucleotide-binding contribution to glycyl-tRNA synthesis. Reason: The InterPro inference correctly identifies a nucleotide-binding enzyme, but ATP is the experimentally established nucleotide substrate. Human structures and biochemical assays show the aminoacylation ATP site and a second ATP site used for Ap4A synthesis. Refine the broad binding term to ATP binding along the verified is_a path. This does not infer ATP binding merely from a protein-family name, nor does it imply that all bound adenylates have the same physiological role. Proposed replacements: ATP binding |
| GO:0004081 bis(5'-nucleosyl)-tetraphosphatase (asymmetrical) activity | IDA PMID:19710017 Crystal structures and biochemical analyses suggest a unique... | MARK AS OVER ANNOTATED | Summary: The cited human GlyRS assays establish Ap4A synthesis rather than the asserted asymmetric hydrolysis. Reason: The original human-enzyme experiments supply ATP and measure Ap4A formation by TLC and mass spectrometry; the crystal structures likewise examine ATP condensation and nucleotide binding. The complete main Experimental Procedures and Discussion and the inspected supplemental Methods/captions distinguish this synthesis reaction from a separately added inorganic pyrophosphatase reagent and from an E. coli Ap4A hydrolase encoded by a different gene. These positive source distinctions do not demonstrate the asserted human GARS1 Ap4A-to-ATP-plus-AMP reaction. Mark this source-specific IDA claim as over-annotated, while retaining the independently supported synthesis annotations. This does not establish that human GARS1 is incapable of hydrolysis under other conditions; that biological question remains open. Supporting Evidence: PMID:19710017 the formation of Ap4A by human GlyRS requires only ATP |
| GO:0004812 aminoacyl-tRNA ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: Glycine-tRNA ligase activity specifies the broad aminoacyl-tRNA ligase inference. Reason: Direct human enzyme assays establish ATP-dependent glycine attachment to cognate tRNA, and tRNA-bound structures explain the recognition and catalytic cycle. GO:0004820 is a verified is_a child of aminoacyl-tRNA ligase activity. The original InterPro entities remain unchanged; the replacement identifies the measured amino-acid specificity rather than attributing an unrelated activity to every family member. Proposed replacements: glycine-tRNA ligase activity |
| GO:0004820 glycine-tRNA ligase activity | EXP PMID:24898252 Cocrystal structures of glycyl-tRNA synthetase in complex wi... | ACCEPT | Summary: Human GlyRS–tRNA complexes and activity measurements support glycine charging. Reason: The original work analyzes human GlyRS with tRNA(Gly), glycine and nucleotide analogues, with functional assays distinguishing catalytic conformations. Its preparations include a cytosolic construct described as residues56–739 and an engineered shorter construct114–739, including mutant complexes. These are experimental constructs, not extra natural products, and the one-residue difference from the current alternative-initiation product boundary is retained as source-coordinate scope. The activity is independently supported by wild-type enzyme studies. |
| GO:0004820 glycine-tRNA ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The ancestral glycine-tRNA ligase assertion is retained by the actual human target. Reason: The exact 739-residue P41250 target is AN21/PTN002473369 in the retained PTHR10745 tree. It descends from the actual IBD at AN0/PTN000078673 for this term; the literal donor set matches the incoming annotation and no retained negative assertion lies on the target path. Human enzymatic and structural work independently establishes glycine charging. The target appearing among the experimental donors is legitimate grounding, not circularity, and no lineage-specific loss is evident. |
| GO:0004820 glycine-tRNA ligase activity | IDA PMID:17544401 Crystal structure of human wildtype and S581L-mutant glycyl-... | ACCEPT | Summary: The human wild-type enzyme has glycine-tRNA ligase activity. Reason: The authentic primary abstract reports structural and functional characterization of human wild-type GlyRS alongside S581L. Independent human aminoacylation assays and tRNA complexes directly support the same activity. The initial paper’s disease interpretation of S581L is separable from wild-type catalysis; later functional/segregation work questions that variant attribution. No unread full Methods or exact modern isoform mapping is claimed for this source. |
| GO:0004820 glycine-tRNA ligase activity | IDA PMID:17545306 Long-range structural effects of a Charcot-Marie-Tooth disea... | ACCEPT | Summary: Human GlyRS directly aminoacylates tRNA with glycine. Reason: The original aminoacylation Methods assay purified human enzyme with ATP, radiolabeled glycine and bovine total tRNA; the study compares wild-type enzyme with a neuropathy-associated mutant. This is direct catalytic evidence for glycine charging, supported independently by later cognate-tRNA complexes. The heterologous tRNA assay substrate and engineered/tagged enzyme preparations are not mislabeled as an endogenous human compartment assay. |
| GO:0004820 glycine-tRNA ligase activity | IDA PMID:19710017 Crystal structures and biochemical analyses suggest a unique... | ACCEPT | Summary: The Ap4A study retains independently established glycine-tRNA ligase activity. Reason: This source studies a human GlyRS enzyme and compares its nucleotide chemistry and tRNA-dependent behavior. Its Ap4A synthesis mechanism is a separate reaction from aminoacylation, not a reason to discard the enzyme’s glycine-charging function. Direct human aminoacylation assays and tRNA-bound structures independently establish the whole claim. This acceptance does not use the Ap4A assay as if it directly measured every step of tRNA charging. |
| GO:0004820 glycine-tRNA ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic glycine-tRNA ligase assignment agrees with direct human enzyme evidence. Reason: The ARBA, ortholog, EC and Rhea support entities identify the glycine-charging reaction. Recombinant human GlyRS catalyzes glycine attachment to tRNA, and a tRNA-bound human enzyme has been structurally characterized. The inference therefore describes the conserved catalytic function; the unaltered upstream supporting entities remain distinct from the independent human experiments used to adjudicate it. |
| GO:0004820 glycine-tRNA ligase activity | IMP PMID:28675565 Compound heterozygosity for loss-of-function GARS variants r... | ACCEPT | Summary: Human loss-of-function variants support the enzyme’s glycine-charging role. Reason: The authentic report identifies a frameshift-associated protein deficit and an R310Q-associated loss of tRNA charging in a compound-heterozygous multisystem disorder. This perturbs the product’s catalytic work, and direct wild-type aminoacylation assays independently establish that work. The recessive loss-of-function mechanism is not generalized to every dominant neuropathy variant, some of which retain charging and acquire other interactions. Supporting Evidence: PMID:28675565 missense variant reduces GARS tRNA charging activity |
| GO:0005515 protein binding | IPI PMID:17545306 Long-range structural effects of a Charcot-Marie-Tooth disea... | REMOVE | Summary: Retain the mixed-species GlyRS association without the uninformative protein-binding term. Reason: The original experiment expresses V5-tagged human GlyRS in mouse N2a cells and co-immunoprecipitates endogenous mouse GlyRS. That is positive association evidence and the literal Q9CZD3 partner is retained. Bare protein binding does not describe a functional specificity; its removal does not negate the interaction. The mixed human–mouse pair is not silently relabeled as two identical human subunits. Human homodimer formation is independently represented by the self-binding and dimerization contexts. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17595294 Charcot-Marie-Tooth disease-associated mutant tRNA synthetas... | REMOVE | Summary: Retain the human–mouse GlyRS association while removing the bare binding term. Reason: The source examines wild-type and neuropathy-associated human GlyRS dimer behavior and interactions in mouse neuronal cells. The original Q9CZD3 partner marks a mixed-species experimental association, not a native human heterodimeric pathway. Positive association is retained, but protein binding is insufficiently informative as a functional annotation. The separately supported human homodimer claims are handled in their own original contexts, without changing this partner identity. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the BATF screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q16520 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the SOCS4 screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q8WXH5 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the KLF6 screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q99612 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the SPAG8 isoform2 screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q99932-2 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the PCDHGC3 screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q9BR81 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Preserve the COPS3 screen association without a bare protein-binding annotation. Reason: The exact human GARS1–Q9UNS2 pair is present in the retained IntAct records for this primary interaction study, with array, pooling and validated two-hybrid records. The original partner and its isoform suffix, where present, remain literal. These positive screen associations do not by themselves identify a specific functional binding class or assign GARS1 the partner’s pathway role. Remove the uninformative protein-binding term while retaining the experimental association and its yeast assay context. Supporting Evidence: |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is integral to GARS1’s aminoacylation chemistry. Reason: ATP supplies the activated adenylate intermediate used to attach glycine to tRNA. Human nucleotide-bound structures and biochemical assays directly establish ATP recognition; the Ap4A study also resolves a second ATP site. Retain this core binding contribution without confusing ATP dependence with an autonomous ATPase activity or assigning the secondary synthesis reaction an established in-vivo role. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The curated secreted-location mapping is supported as a non-core occurrence. Reason: The UniProt location-vocabulary inference agrees with the separately inspected mouse secretion evidence, which distinguishes differentiated myotubes from undifferentiated myoblasts and reports extracellular protein with assay controls. Retain the extracellular location as non-core without claiming universal secretion, a classical signal peptide or normal receptor activity. This occurrence does not conflict with the principal intracellular aminoacylation pools. The broad location accommodates the reported released and vesicle-associated pools together; the inspected evidence does not establish that all extracellular protein occupies a particular nonvesicular extracellular-space compartment. |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog secretion supports a limited extracellular GlyRS pool. Reason: The mouse Q9CZD3 source chain leads to PMID:26503042. Its inspected extended-data captions report endogenous extracellular GlyRS from motor-neuron-like cells and differentiated myotubes, with secretion controls, and include transfected wild-type protein. This supports nonexclusive extracellular occurrence rather than a core secretion function. Disease-mutant neuropilin binding is a separate neomorphic result and is not transferred to normal human GARS1. The species and culture-system boundary remains explicit. The broad location accommodates the reported released and vesicle-associated pools together; the inspected evidence does not establish that all extracellular protein occupies a particular nonvesicular extracellular-space compartment. Supporting Evidence: |
| GO:0005737 cytoplasm | EXP PMID:17035524 Functional analyses of glycyl-tRNA synthetase mutations sugg... | MODIFY | Summary: Independent cytosol evidence refines the broad cellular localization observed in this study. Reason: The inspected original Results show endogenous human GARS in cell-body and neurite granules and diffuse cellular staining, while engineered short-form constructs have their own localization limits. Granules are not automatically secretory granules. The original observation supports cytoplasm; the added cytosol precision is grounded independently in alternative-initiation/localization experiments and the actual target reaction model. Preserve that division of evidence rather than claiming a specific cytosol assay or mitochondrial exclusion from every image. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | EXP PMID:17529987 Cytoplasmic and mitochondrial protein translation in axonal ... | MODIFY | Summary: The nonmitochondrial pool is more precisely represented as cytosol. Reason: The authentic source abstract describes cytoplasmic and mitochondrial translation and human/Drosophila GlyRS forms in the context of fly neuronal arborization; the full human construct-specific localization panel was not independently inspected. Independent human localization work and the cytosolic GARS reaction chain establish the more precise cytosol setting. The original experimental context remains unchanged, with no assertion that a fly phenotype alone proves a human image or that cytosol is the only GARS1 compartment. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | EXP PMID:26327585 Elaborate uORF/IRES features control expression and localiza... | MODIFY | Summary: Alternative-initiation experiments support a cytosolic GARS1 pool. Reason: The selected original experiments distinguish transcript-leader regulation from protein alternative initiation and test expression/localization in mammalian cells and in vitro. Translation of the cytosolic form can occur near ER-bound ribosomes, but the fractionation result excludes ER copurification; this is not evidence of ER-lumen residence or integral membrane insertion. Cytosol refines the original broad cytoplasm term by a verified part_of relation. Transcript mRNA1/mRNA2 numbering is not substituted for current protein isoform numbering. Proposed replacements: cytosol Supporting Evidence: |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | MODIFY | Summary: Cytosol specifies the supported nonorganellar GARS1 pool. Reason: The actual cytoplasm IBD at AN0/PTN000078673 is inherited by the exact human target, with legitimate self-donor evidence and no path loss. Human expression/localization studies and the target-specific cytosolic reaction model independently support a nonorganellar pool. Refine to cytosol through the verified part_of relation; this does not erase the separate mitochondrial product or relocate every molecule to cytosol. The original broad IBA and complete donor set remain intact. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | MODIFY | Summary: Cytosol is the supported specific setting for the nonmitochondrial enzyme pool. Reason: The electronic cytoplasm claim is biologically sound. Human alternative-initiation/localization experiments and the cytosolic aminoacylation model identify a nonorganellar pool, permitting the verified cytosol part_of cytoplasm refinement. The distinct mitochondrial pool is retained elsewhere; no absence-of-targeting heuristic is used to make cytosol an exclusive localization. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | TAS PMID:7961834 Primary structure and functional expression of human Glycyl-... | MODIFY | Summary: Independent localization evidence supplies cytosol precision beyond the early cloning report. Reason: The authentic early paper identifies and functionally expresses a human GlyRS sequence of 685 residues; its abstract establishes enzyme identity and activity, not a new high-resolution localization experiment. Later human alternative-initiation/localization evidence and the curated cytosolic reaction model support the cytosol refinement of this broad TAS claim. The original reference remains intact and is not credited with an unread compartment assay. Proposed replacements: cytosol |
| GO:0005739 mitochondrion | EXP PMID:17529987 Cytoplasmic and mitochondrial protein translation in axonal ... | ACCEPT | Summary: Mitochondrial GARS1 is supported despite the limited independently read scope of this source. Reason: The authentic PMID:17529987 abstract reports cytoplasmic and mitochondrial GlyRS forms and their roles in neuronal terminal arborization, with substantial Drosophila context. The exact human localization panel was not inspected, so no detailed construct or image claim is made. Independent human alternative-initiation/localization evidence and the target-specific matrix reaction model support the whole mitochondrial claim. Retain the original experimental annotation and root-organelle term rather than using incomplete access to challenge it. |
| GO:0005739 mitochondrion | EXP PMID:26327585 Elaborate uORF/IRES features control expression and localiza... | ACCEPT | Summary: Human alternative-initiation experiments establish a mitochondrial enzyme pool. Reason: The original study distinguishes two transcript leaders and tests how they affect use of the cytosolic and mitochondrial initiation sites. The leader names are not protein isoform IDs. Its localization and translation experiments support the organelle claim alongside the distinct cytosolic pool; they do not imply that every expressed construct or transcript is equally mitochondrial. Preserve mitochondrion as a valid root-organelle term. Supporting Evidence: PMID:26327585 both the cytosolic and mitochondrial forms of GARS |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: Independent human evidence supports the mitochondrial claim in the proteomic context. Reason: The authentic MitoCoP abstract describes a quantitative high-confidence human mitochondrial proteome, but the exact GARS1 target table row was not independently inspected. This source limit does not refute the curator’s HTP assertion. Human localization/alternative-initiation experiments and the mitochondrial charging model independently establish the same organelle location. Retain the true claim with explicit source scope, without inventing target abundance, fractionation enrichment or peptide measurements. |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial organelle assertion is supported by descent and human localization evidence. Reason: The exact human target descends from AN3/PTN000078675 carrying the mitochondrial IBD, including human experimental grounding among the literal donors. Independent alternative-initiation/localization work and the mitochondrial aminoacylation model support this pool. Retain the true root-organelle claim rather than replacing it by a subcompartment; matrix evidence can inform the core location without invalidating mitochondrion. |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: The mitochondrial location-vocabulary inference is biologically supported. Reason: Human GARS1 supplies a mitochondrial enzyme pool through alternative initiation, supported by localization experiments and the matrix aminoacylation model. The literal UniProt mapping is retained as a true root-organelle claim, without replacement by matrix. The 739-residue precursor sequence and its processing are distinguished from the shorter 685-residue alternative-initiation product. |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-380240 | ACCEPT | Summary: The actual human GARS reaction is modeled in the mitochondrial matrix. Reason: The retained official chain R-HSA-380240→catalyst379584→dimer379593→protein379650 reaches UniProt P41250 with GO:0005759 compartment. Two component occurrences encode the dimer. This is direct verification of model membership and compartment, supported by independent mitochondrial localization and charging biology. The modeled37–739 processed chain is preserved as the model’s coordinate choice, not asserted to be the exact alternate-initiation product or an independently read cleavage assay. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: The cytosolic enzyme pool is independently supported. Reason: The HPA-based IDA is retained with its original source. Its specific images were not independently inspected here, but human alternative-initiation/localization evidence and the verified cytosolic GARS reaction chain establish the same pool. The existence of a mitochondrial form does not contradict nonexclusive cytosol localization. No image-level claim or exclusive cytosolic distribution is inferred from the electronic record. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-380048 | ACCEPT | Summary: The cytosolic charging reaction contains the actual human GARS1 entity. Reason: The official chain R-HSA-380048→catalyst379594→dimer379600→protein379574 reaches UniProt P41250 in GO:0005829 cytosol. The model contains two copies of the same protein. Its residue37–739 entity is not equated with the currently verified55–739 alternative-initiation product; model-coordinate uncertainty does not erase the independently supported cytosolic pool. Retain the original TAS annotation and model bytes. |
| GO:0006418 tRNA aminoacylation for protein translation | IEA GO_REF:0000120 | ACCEPT | Summary: Glycine charging directly performs tRNA aminoacylation for translation. Reason: GARS1 attaches glycine to cognate tRNAs using ATP and therefore performs a step of the annotated process. The electronic ARBA/InterPro inference is independently grounded in human enzyme assays and tRNA complexes. Because the former glycine-specific process term is obsolete as a restatement of molecular function, the current general process is retained alongside the specific glycine-tRNA ligase molecular activity. |
| GO:0006418 tRNA aminoacylation for protein translation | IMP PMID:28675565 Compound heterozygosity for loss-of-function GARS variants r... | ACCEPT | Summary: Loss of GARS1 charging activity perturbs the performed tRNA-aminoacylation step. Reason: The human variant study reports impaired charging and protein loss, supported by independently demonstrated wild-type glycine-tRNA ligase chemistry. The product itself carries out the aminoacylation reaction; this is not a process assignment based solely on disease necessity. Mitochondrial respiratory-chain dysfunction is a downstream consequence and is not treated as a new GARS1 catalytic activity. |
| GO:0006426 obsolete glycyl-tRNA aminoacylation | IEA GO_REF:0000002 | MODIFY | Summary: Replace the obsolete glycine-specific process term while preserving its original assertion. Reason: The current ontology marks GO:0006426 obsolete because it restates glycine-tRNA ligase activity; its comment directs the biological process to tRNA aminoacylation for protein translation. GARS1 directly catalyzes the relevant charging step. Preserve the literal incoming obsolete ID and its InterPro context, proposing GO:0006418 as the current process representation rather than silently rewriting the machine field or inventing a hierarchical edge from an obsolete term. Proposed replacements: tRNA aminoacylation for protein translation |
| GO:0015966 diadenosine tetraphosphate biosynthetic process | IDA PMID:19710017 Crystal structures and biochemical analyses suggest a unique... | KEEP AS NON CORE | Summary: Ap4A production is directly demonstrated, with physiological contribution unresolved. Reason: Purified human GlyRS produces Ap4A from ATP, so it performs the biosynthetic reaction rather than merely being affected by the product. The paper proposes a homeostatic role but does not establish its in-vivo flux, tissue necessity or compartment-specific contribution. Retain this source-specific secondary process as non-core; it does not warrant a second physiological core solely because the assay is positive. Supporting Evidence: |
| GO:0030141 secretory granule | IEA GO_REF:0000107 | UNDECIDED | Summary: The secretory-granule donor does not yet identify the current GARS1 protein unambiguously. Reason: The human IEA transfers a mouse Q9CZD3 location whose original source is PMID:8939962. Recovered original experiments positively detect dense-granule fractionation and stimulated release of 23-kDa material using A61 antibodies, with a five-residue LysC sequence match. The deposited A61 plus-strand CDS encodes 114 residues that are not a contiguous current Gars1 peptide. Its 342-nt sequence instead has strong reverse-complement correspondence within the current mouse Gars1 CDS; the current RefSeq explicitly retains PMID:8939962 and the Sgrp23 alias. These facts preserve the historical linkage but do not identify the purified granule protein as current full-length Gars1 or a defined processed product. Retain UNDECIDED, without asserting a wrong gene, clone error or natural antisense transcript. The reproducible A61 comparison is provided in the cited local analysis; the release and peptide observations come from the selected original Methods/Results and Figure 2/3 captions, not merely the cached abstract. |
| GO:0030424 axon | IDA PMID:17035524 Functional analyses of glycyl-tRNA synthetase mutations sugg... | KEEP AS NON CORE | Summary: Human axon localization is observed in the source tissue experiments. Reason: Selected original Results and textual captions describe endogenous GARS granules in human peripheral axons and motor-neuron processes, with normal human tissue, neurofilament labeling and peptide-blocking controls. This is positive localization evidence, not merely a neuropathy phenotype or transfected mutant distribution. Retain axon as a non-core cell-type-specific occurrence without asserting an independent motor/transport activity or product-specific localization from the available antibody experiments. Supporting Evidence: PMID:17035524 peripheral nerve axons of normal human tissue |
| GO:0030424 axon | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Axonal GARS1 is a directly supported neuronal location. Reason: The original human study reports endogenous GARS staining in normal adult spinal cord and sural-nerve axons, with neurofilament colabeling and antibody controls. This supports the curated axon-vocabulary mapping as a nonexclusive location in a specialized cell type. It does not independently demonstrate axonal transport or prove that all local granules perform aminoacylation. The conserved catalytic core remains broader than this neuronal compartment. Supporting Evidence: |
| GO:0042802 identical protein binding | IPI PMID:17545306 Long-range structural effects of a Charcot-Marie-Tooth disea... | MODIFY | Summary: Protein homodimerization specifies the independently supported human self-association. Reason: The original self-partner context is consistent with human GlyRS dimer formation. Crystallographic interfaces, solution ultracentrifugation and biochemical work establish homodimeric assembly; the crystal’s asymmetric-unit count is not used as a substitute for assembly evidence. GO:0042803 is a verified is_a descendant of identical protein binding. The separate human–mouse co-IP is kept as mixed-species evidence rather than being the sole basis for this homodimer refinement. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:17545306 homodimeric human GlyRS |
| GO:0042802 identical protein binding | IPI PMID:17595294 Charcot-Marie-Tooth disease-associated mutant tRNA synthetas... | MODIFY | Summary: Homodimerization is the informative form of GlyRS self-binding. Reason: The original study compares human wild-type and mutant dimer interfaces and oligomeric behavior, while independent structural and solution evidence establishes the wild-type homodimer. Replace identical protein binding by its verified homodimerization descendant. Variable mutant effects do not imply that all disease variants lose dimerization, and the original self-partner identity remains unchanged. Proposed replacements: protein homodimerization activity |
| GO:0046983 protein dimerization activity | IDA PMID:17544401 Crystal structure of human wildtype and S581L-mutant glycyl-... | MODIFY | Summary: The human enzyme’s dimer is a homodimer. Reason: The primary report concerns human wild-type and S581L GlyRS structure and activity; independent human structure, solution and interaction experiments establish homodimeric assembly. Protein homodimerization activity is a verified is_a child of protein dimerization activity and states the supported subunit relationship. This refinement does not rely on the historical pathogenicity label for S581L, nor claim that its exact assay construct is a distinct natural isoform. Proposed replacements: protein homodimerization activity |
| GO:0046983 protein dimerization activity | IDA PMID:17545306 Long-range structural effects of a Charcot-Marie-Tooth disea... | MODIFY | Summary: Protein homodimerization specifies measured GlyRS dimer formation. Reason: The inspected original Results describe wild-type dimeric behavior and its mutation-dependent alteration, supported by solution measurements and a structurally extensive interface. The informative descendant is protein homodimerization activity. A one-subunit crystallographic asymmetric unit does not negate the biological assembly, and enhanced mutant dimerization is distinguished from the wild-type catalytic role. Proposed replacements: protein homodimerization activity Supporting Evidence: |
| GO:0070062 extracellular exosome | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The Ensembl transfer preserves a limited experimentally grounded vesicle occurrence. Reason: The electronic ortholog transfer concerns the same mouse GlyRS vesicle/secretion experiments, not a UniProt cellular-component vocabulary rule. The inspected original fractionation and secretion captions support extracellular-vesicle association under those culture conditions. Retain the non-core occurrence with the species/assay boundary; do not infer integral membrane insertion, luminal topology or a new human secretory function from fraction membership alone. Supporting Evidence: |
| GO:0070062 extracellular exosome | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The ortholog study supports an extracellular-vesicle-associated GlyRS pool. Reason: The mouse source chain leads to the inspected PMID:26503042 extended-data experiments. GlyRS is detected in an exosome-enriched differential-centrifugation fraction with TSG101 and other fraction controls, and secretion responds to the reported pharmacological manipulations. This supports a limited non-core vesicle association; it does not establish exclusive vesicle localization, membrane topology or a universal secretion mechanism. Wild-type secretion is distinct from the paper’s disease-mutant neomorphic receptor binding. Supporting Evidence: |
| GO:0070150 obsolete mitochondrial glycyl-tRNA aminoacylation | IBA GO_REF:0000033 | MODIFY | Summary: Retain the mitochondrial charging inference using the current process term. Reason: The actual PTHR10745 assertion is at AN3/PTN000078675, an ancestor of the exact human AN21 target; its PomBase and SGD donor set is unchanged and no loss assertion lies on the retained path. GO:0070150 is now obsolete as a restatement of molecular specificity, and its official comment points to mitochondrial tRNA aminoacylation. Propose GO:0070127 while preserving the original ID and phylogenetic evidence. This is a term-maintenance correction, not a challenge based on donor count or absence of human self-evidence. Proposed replacements: tRNA aminoacylation for mitochondrial protein translation |
| GO:0141192 ATP:ATP adenylyltransferase activity | EXP PMID:19710017 Crystal structures and biochemical analyses suggest a unique... | KEEP AS NON CORE | Summary: Human GlyRS directly catalyzes ATP-dependent Ap4A synthesis in vitro. Reason: The inspected synthesis experiments, product TLC/mass-spectrometry analysis and nucleotide complexes support direct ATP condensation. Cognate tRNA inhibits this alternative reaction; its structural explanation is distinguished from a demonstrated cellular regulatory mechanism. The reaction is genuine biochemical capacity, but the physiological magnitude and compartment-specific contribution are unresolved, so it remains non-core. No hydrolase activity is inferred from these synthesis data. Supporting Evidence: PMID:19710017 direct condensation of two ATPs |
| GO:0141192 ATP:ATP adenylyltransferase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Direct ATP condensation is a demonstrated secondary biochemical capacity. Reason: The Rhea-based electronic assignment agrees with the primary human enzyme experiments: GlyRS produces Ap4A by condensation of two ATP molecules independently of glycine. This is a measured reaction, not a guessed reversal of aminoacylation. Its proposed contribution to intracellular Ap4A homeostasis is not established by the purified assay; retain the activity as non-core while keeping glycine charging as the conserved core. Supporting Evidence: |
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Download this section (compressed HTML)Q: Does purified human GARS1 catalyze Ap4A hydrolysis independently of its ATP-condensation reaction, and under which substrate and cofactor conditions?
Q: What fraction of cellular Ap4A synthesis is attributable to GARS1 when physiological tRNA concentrations compete with the ATP-condensation reaction?
Q: Can sequence-resolved proteomics establish the identity of the historical 23-kDa A61-reactive secretory-granule protein and its relationship, if any, to current mouse Gars1 products?
Experiment: Assay sequence-verified human GARS1 with separately supplied ATP or purified Ap4A, matched enzyme-free and reagent controls, and quantitative product identification across a tRNA titration.
Hypothesis: Ap4A synthesis and any hydrolysis can be distinguished from separate phosphatase reagents and tRNA competition.
Experiment: Recover the A61-reactive granule fraction and identify multiple unique peptides against both current mouse Gars1 products and the original submitted A61 translation, retaining stimulation and fraction-purity controls.
Hypothesis: The historical granule-protein identity can be resolved at the peptide rather than database-alias level.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether human GARS1 itself catalyzes asymmetric Ap4A hydrolysis under defined conditions is not established by the synthesis assays inspected here.
BIOLOGY
What is known: ATP-dependent Ap4A synthesis is directly demonstrated; a separately added inorganic pyrophosphatase and a bacterial hydrolase discussion do not establish human GARS1 hydrolysis.
What would resolve it: Separate ATP-fed synthesis from purified-Ap4A hydrolysis assays with matched enzyme-free and phosphatase controls and quantitative product identification.
Provenance (the field's own admissions):
Gap: The molecular identity of the A61-reactive 23-kDa mouse granule protein, and its relationship to current Gars1 products, remains unresolved.
BIOLOGYCURATION
What is known: Original fractionation, stimulated release and peptide observations are positive. The historical nucleotide fragment corresponds in reverse-complement orientation to current Gars1 CDS, but its declared plus-strand translation is not a contiguous current Gars1 peptide.
What would resolve it: Identify multiple unique peptides from the A61-reactive granule material against both the historical submitted translation and current Gars1 products.
Provenance (the field's own admissions):
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