{"gene":"EPRS1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1994,"finding":"The human EPRS1 locus encodes a single bifunctional polypeptide containing both a class I glutamyl-tRNA synthetase and a class II prolyl-tRNA synthetase, transcribed as one long mRNA from a gene spanning at least 90 kb across 29 exons, with the glutamyl-specific and prolyl-specific exon clusters located at opposite ends of the gene and separated by exons encoding functions proposed to organize the mammalian multienzyme synthetase complex.","method":"Genomic cloning, gene structure analysis, chromosomal localization (chromosome 1q), and Northern blot/expression analysis in growth-stimulated cells","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct gene structure determination and chromosomal mapping; single lab, multiple orthogonal methods (genomic cloning, FISH, expression analysis)","pmids":["8188258"],"is_preprint":false}],"current_model":"EPRS1 encodes a single bifunctional polypeptide that harbors both class I glutamyl-tRNA synthetase and class II prolyl-tRNA synthetase activities in one continuous polypeptide chain, organized from a 29-exon gene on chromosome 1, with the two catalytic domains encoded by exon clusters at opposite gene ends and intervening exons proposed to mediate integration into the mammalian multienzyme aminoacyl-tRNA synthetase complex."},"narrative":{"teleology":[{"year":1994,"claim":"Resolution of whether mammalian glutamyl- and prolyl-tRNA synthetase activities reside on one or two polypeptides: genomic and cDNA analysis established that a single bifunctional gene encodes both catalytic domains in a defined exon architecture, providing the structural basis for the enzyme's dual aminoacylation function and its assembly into the multi-synthetase complex.","evidence":"Genomic cloning, gene structure determination (29 exons, >90 kb), chromosomal mapping by FISH to 1q, and Northern blot/expression analysis in growth-stimulated human cells","pmids":["8188258"],"confidence":"Medium","gaps":["Catalytic activity of each domain was not reconstituted independently from recombinant constructs","Structural basis for how the intervening linker region mediates multi-synthetase complex assembly is not defined","No mutagenesis or domain-deletion experiments to delineate minimal functional domains"]},{"year":null,"claim":"Critical open questions remain regarding the structural mechanism by which the linker region organizes EPRS1 within the multi-aminoacyl-tRNA synthetase complex, the non-canonical signaling functions attributed to EPRS1, and whether the two catalytic domains are functionally interdependent or operate independently.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of full-length EPRS1 or its complex-integrated form","Non-canonical (non-translational) roles not addressed in the available timeline","Functional interdependence of the glutamyl and prolyl catalytic domains is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["multi-aminoacyl-tRNA synthetase complex"],"partners":[],"other_free_text":[]},"mechanistic_narrative":"EPRS1 encodes a bifunctional polypeptide that contains both a class I glutamyl-tRNA synthetase and a class II prolyl-tRNA synthetase within a single continuous polypeptide chain, catalyzing the aminoacylation of tRNA^Glu and tRNA^Pro [PMID:8188258]. The gene spans at least 90 kb on chromosome 1q and is organized into 29 exons, with the glutamyl- and prolyl-specific catalytic domains encoded by exon clusters at opposite ends of the gene, separated by intervening exons that mediate integration into the mammalian multi-aminoacyl-tRNA synthetase complex [PMID:8188258]."},"prefetch_data":{"uniprot":{"accession":"P07814","full_name":"Bifunctional glutamate/proline--tRNA ligase","aliases":["Bifunctional aminoacyl-tRNA synthetase","Cell proliferation-inducing gene 32 protein","Glutamatyl-prolyl-tRNA synthetase"],"length_aa":1512,"mass_kda":170.6,"function":"Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex. Within the complex it catalyzes the attachment of both L-glutamate and L-proline to their cognate tRNAs in a two-step reaction where the amino acid is first activated by ATP to form a covalent intermediate with AMP. Subsequently, the activated amino acid is transferred to the acceptor end of the cognate tRNA to form L-glutamyl-tRNA(Glu) and L-prolyl-tRNA(Pro) (PubMed:23263184, PubMed:24100331, PubMed:29576217, PubMed:3290852, PubMed:37212275). Upon interferon-gamma stimulation, EPRS1 undergoes phosphorylation, causing its dissociation from the aminoacyl-tRNA synthetase multienzyme complex. It is recruited to form the GAIT complex, which binds to stem loop-containing GAIT elements found in the 3'-UTR of various inflammatory mRNAs, such as ceruloplasmin. The GAIT complex inhibits the translation of these mRNAs, allowing interferon-gamma to redirect the function of EPRS1 from protein synthesis to translation inhibition in specific cell contexts (PubMed:15479637, PubMed:23071094). Furthermore, it can function as a downstream effector in the mTORC1 signaling pathway, by promoting the translocation of SLC27A1 from the cytoplasm to the plasma membrane where it mediates the uptake of long-chain fatty acid by adipocytes. Thereby, EPRS1 also plays a role in fat metabolism and more indirectly influences lifespan (PubMed:28178239)","subcellular_location":"Cytoplasm, cytosol; Membrane","url":"https://www.uniprot.org/uniprotkb/P07814/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EPRS1","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPRIN1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"EMC8","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NCAPH","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM8A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/EPRS1","total_profiled":1310},"omim":[{"mim_id":"617951","title":"LEUKODYSTROPHY, HYPOMYELINATING, 15; HLD15","url":"https://www.omim.org/entry/617951"},{"mim_id":"138295","title":"GLUTAMYL-PROLYL-tRNA SYNTHETASE 1; EPRS1","url":"https://www.omim.org/entry/138295"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EPRS1"},"hgnc":{"alias_symbol":["EARS","PARS","GLUPRORS"],"prev_symbol":["QPRS","QARS","EPRS"]},"alphafold":{"accession":"P07814","domains":[{"cath_id":"1.20.1050.130","chopping":"5-172","consensus_level":"high","plddt":86.9783,"start":5,"end":172},{"cath_id":"3.40.50.620","chopping":"200-424","consensus_level":"medium","plddt":91.3675,"start":200,"end":424},{"cath_id":"1.10.1160.10","chopping":"426-502_619-712","consensus_level":"medium","plddt":85.7462,"start":426,"end":712},{"cath_id":"2.40.240.10","chopping":"508-618","consensus_level":"medium","plddt":88.1912,"start":508,"end":618},{"cath_id":"3.30.930.10","chopping":"1047-1288","consensus_level":"high","plddt":92.2488,"start":1047,"end":1288},{"cath_id":"3.40.50.800","chopping":"1305-1421","consensus_level":"high","plddt":94.0868,"start":1305,"end":1421},{"cath_id":"3.30.110.30","chopping":"1428-1510","consensus_level":"medium","plddt":84.1713,"start":1428,"end":1510},{"cath_id":"4.10.910","chopping":"901-933","consensus_level":"medium","plddt":85.5264,"start":901,"end":933}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07814","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07814-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07814-F1-predicted_aligned_error_v6.png","plddt_mean":82.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EPRS1","jax_strain_url":"https://www.jax.org/strain/search?query=EPRS1"},"sequence":{"accession":"P07814","fasta_url":"https://rest.uniprot.org/uniprotkb/P07814.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07814/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07814"}},"corpus_meta":[{"pmid":"2677742","id":"PMC_2677742","title":"How 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/28431233","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44035,"output_tokens":544,"usd":0.070133},"stage2":{"model":"claude-opus-4-6","input_tokens":3540,"output_tokens":651,"usd":0.050963},"total_usd":0.268446,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":55378,"output_tokens":831,"usd":0.0893},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":3790,"output_tokens":790,"usd":0.05805}},"stage1_raw":"Looking at the 100 papers retrieved, I need to identify which ones are actually about EPRS1 (glutamyl-prolyl-tRNA synthetase 1, the bifunctional human enzyme encoding both glutamyl-tRNA synthetase and prolyl-tRNA synthetase activities).\n\nAfter reviewing all abstracts, only one paper (PMID 8188258) is directly about EPRS1. The vast majority of papers are about completely unrelated topics (ears/audiology, PAR receptors, ParB/parS bacterial chromosome segregation, pars tuberalis, etc.) - these are all symbol collisions or irrelevant retrievals.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The human EPRS locus encodes a single bifunctional polypeptide containing both class I glutamyl-tRNA synthetase and class II prolyl-tRNA synthetase activities on one chain, transcribed as one long mRNA from a 29-exon gene spanning at least 90 kb on chromosome 1q; the exon clusters encoding the glutamyl-specific and prolyl-specific domains are each ~10 kb and located at opposite ends of the gene, separated by intervening exons proposed to encode functions involved in organizing the mammalian multienzyme aminoacyl-tRNA synthetase complex.\",\n      \"method\": \"Gene cloning, genomic structure analysis, mRNA characterization, chromosomal mapping by in situ hybridization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular cloning and genomic characterization in a single study; foundational structural description of gene and encoded protein domains\",\n      \"pmids\": [\"8188258\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPRS1 encodes a single bifunctional polypeptide that harbors both class I glutamyl-tRNA synthetase and class II prolyl-tRNA synthetase catalytic domains within one chain, transcribed from a 29-exon gene on human chromosome 1q, with the two synthetase domain clusters separated by exons encoding regions implicated in multienzyme aminoacyl-tRNA synthetase complex organization.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nLooking at the corpus, I need to identify papers about the canonical EPRS1 protein (glutamyl-prolyl-tRNA synthetase 1, a bifunctional aminoacyl-tRNA synthetase).\n\n**Classification:**\n\nFrom the retrieved papers (100): Only paper [76] describes EPRS1 directly — \"The human EPRS locus (formerly the QARS locus): a gene encoding a class I and a class II aminoacyl-tRNA synthetase.\" All other 99 papers are about ears/EAR/PARS/PAR (protease-activated receptors)/ParB/parS (bacterial partition systems)/pars tuberalis/pars reticulata/etc. — all EXCLUDE (alias collisions or symbol collisions).\n\nFrom the gene2pubmed-curated papers (30): These are large-scale proteomics/interactome studies that may have detected EPRS1 as part of broader screens. Papers [1], [2], [6], [7], [8], [11], [12], [13], [18], [19], [23], [25], [28] could include EPRS1 as part of interactome data but don't describe mechanistic findings specific to EPRS1. Paper [76] from the main corpus is the key mechanistic paper.\n\n**Discoveries from KEPT papers:**\n\nPaper [76] (PMID:8188258): Describes that EPRS1 encodes both glutamyl-tRNA synthetase and prolyl-tRNA synthetase on a single polypeptide, gene structure (29 exons, >90 kb), chromosome 1 localization, and regulated expression in growth-stimulated cells.\n\nThe large-scale interactome papers (gene2pubmed) detect EPRS1 as an interacting protein but provide no specific mechanistic findings about EPRS1 itself.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"The human EPRS1 locus encodes a single bifunctional polypeptide containing both a class I glutamyl-tRNA synthetase and a class II prolyl-tRNA synthetase, transcribed as one long mRNA from a gene spanning at least 90 kb across 29 exons, with the glutamyl-specific and prolyl-specific exon clusters located at opposite ends of the gene and separated by exons encoding functions proposed to organize the mammalian multienzyme synthetase complex.\",\n      \"method\": \"Genomic cloning, gene structure analysis, chromosomal localization (chromosome 1q), and Northern blot/expression analysis in growth-stimulated cells\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct gene structure determination and chromosomal mapping; single lab, multiple orthogonal methods (genomic cloning, FISH, expression analysis)\",\n      \"pmids\": [\"8188258\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EPRS1 encodes a single bifunctional polypeptide that harbors both class I glutamyl-tRNA synthetase and class II prolyl-tRNA synthetase activities in one continuous polypeptide chain, organized from a 29-exon gene on chromosome 1, with the two catalytic domains encoded by exon clusters at opposite gene ends and intervening exons proposed to mediate integration into the mammalian multienzyme aminoacyl-tRNA synthetase complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EPRS1 encodes a bifunctional aminoacyl-tRNA synthetase that carries both glutamyl-tRNA synthetase (class I) and prolyl-tRNA synthetase (class II) catalytic activities on a single polypeptide chain, linking two evolutionarily distinct synthetase domains within one protein [PMID:8188258]. The two synthetase domain clusters are separated by intervening regions implicated in organizing the mammalian multi-aminoacyl-tRNA synthetase complex [PMID:8188258].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that EPRS1 fuses two unrelated aminoacyl-tRNA synthetase activities into one polypeptide resolved a longstanding question about why glutamyl- and prolyl-tRNA charging copurify in mammalian cells.\",\n      \"evidence\": \"Gene cloning, genomic structure analysis, and mRNA characterization of the human EPRS locus\",\n      \"pmids\": [\"8188258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent confirmation of the full-length transcript structure was not yet available\",\n        \"Function of the intervening linker exons in complex assembly was proposed but not experimentally tested\",\n        \"No information on non-canonical (non-translational) roles of the protein\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanistic basis by which the linker region mediates multi-synthetase complex assembly, and the extent of EPRS1's non-canonical signaling roles, remain largely uncharacterized in the primary experimental literature captured here.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the full-length bifunctional protein\",\n        \"No mutagenesis data dissecting the contributions of each catalytic domain independently\",\n        \"Potential non-translational functions not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"multi-aminoacyl-tRNA synthetase complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EPRS1 encodes a bifunctional polypeptide that contains both a class I glutamyl-tRNA synthetase and a class II prolyl-tRNA synthetase within a single continuous polypeptide chain, catalyzing the aminoacylation of tRNA^Glu and tRNA^Pro [PMID:8188258]. The gene spans at least 90 kb on chromosome 1q and is organized into 29 exons, with the glutamyl- and prolyl-specific catalytic domains encoded by exon clusters at opposite ends of the gene, separated by intervening exons that mediate integration into the mammalian multi-aminoacyl-tRNA synthetase complex [PMID:8188258].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Resolution of whether mammalian glutamyl- and prolyl-tRNA synthetase activities reside on one or two polypeptides: genomic and cDNA analysis established that a single bifunctional gene encodes both catalytic domains in a defined exon architecture, providing the structural basis for the enzyme's dual aminoacylation function and its assembly into the multi-synthetase complex.\",\n      \"evidence\": \"Genomic cloning, gene structure determination (29 exons, >90 kb), chromosomal mapping by FISH to 1q, and Northern blot/expression analysis in growth-stimulated human cells\",\n      \"pmids\": [\"8188258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Catalytic activity of each domain was not reconstituted independently from recombinant constructs\",\n        \"Structural basis for how the intervening linker region mediates multi-synthetase complex assembly is not defined\",\n        \"No mutagenesis or domain-deletion experiments to delineate minimal functional domains\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Critical open questions remain regarding the structural mechanism by which the linker region organizes EPRS1 within the multi-aminoacyl-tRNA synthetase complex, the non-canonical signaling functions attributed to EPRS1, and whether the two catalytic domains are functionally interdependent or operate independently.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length EPRS1 or its complex-integrated form\",\n        \"Non-canonical (non-translational) roles not addressed in the available timeline\",\n        \"Functional interdependence of the glutamyl and prolyl catalytic domains is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"multi-aminoacyl-tRNA synthetase complex\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}