Affinage

EPRS1

Bifunctional glutamate/proline--tRNA ligase · UniProt P07814

Round 2 corrected
Length
1512 aa
Mass
170.6 kDa
Annotated
2026-04-28
130 papers in source corpus 1 papers cited in narrative 1 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 1 step
  1. 1994 Medium

    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

    PMID:8188258

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 1
Complex memberships
multi-aminoacyl-tRNA synthetase complex

Evidence

Reading pass · 1 per-paper finding extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 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. Genomic cloning, gene structure analysis, chromosomal localization (chromosome 1q), and Northern blot/expression analysis in growth-stimulated cells Genomics Medium 8188258

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2015 Gene essentiality and synthetic lethality in haploid human cells. Science (New York, N.Y.) 657 26472760
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
1989 How the ear's works work. Nature 583 2677742
1999 Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nature genetics 534 10471511
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2008 Thyrotrophin in the pars tuberalis triggers photoperiodic response. Nature 402 18354476
2017 Synergistic drug combinations for cancer identified in a CRISPR screen for pairwise genetic interactions. Nature biotechnology 378 28319085
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2013 3D printed bionic ears. Nano letters 375 23635097
2004 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. The Biochemical journal 372 14744259
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2015 Aerobic glycolysis tunes YAP/TAZ transcriptional activity. The EMBO journal 362 25796446
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2019 Protease-activated receptors (PARs): mechanisms of action and potential therapeutic modulators in PAR-driven inflammatory diseases. Thrombosis journal 288 30976204
2015 Aging after noise exposure: acceleration of cochlear synaptopathy in "recovered" ears. The Journal of neuroscience : the official journal of the Society for Neuroscience 280 25972177
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2012 Regulation of the Hippo-YAP pathway by protease-activated receptors (PARs). Genes & development 249 22972936
2017 A Compendium of RNA-Binding Proteins that Regulate MicroRNA Biogenesis. Molecular cell 248 28431233
2009 Recruitment of SMC by ParB-parS organizes the origin region and promotes efficient chromosome segregation. Cell 241 19450517
2007 Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more. British journal of pharmacology 237 18059329
2008 Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thrombosis and haemostasis 163 18278179
2014 Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. British journal of pharmacology 148 24354792
2011 The walls have ears: the role of plant CrRLK1Ls in sensing and transducing extracellular signals. Journal of experimental botany 127 21252257
2003 RABBIT EARS, encoding a SUPERMAN-like zinc finger protein, regulates petal development in Arabidopsis thaliana. Development (Cambridge, England) 127 14681191
1999 Pars planitis: clinical features and class II HLA associations. Ophthalmology 119 10080220
2014 Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. American journal of human genetics 113 24656866
2019 Self-organization of parS centromeres by the ParB CTP hydrolase. Science (New York, N.Y.) 105 31649139
2003 Melatonin induces Cry1 expression in the pars tuberalis of the rat. Brain research. Molecular brain research 103 12829319
2014 PARS: a web server for the prediction of Protein Allosteric and Regulatory Sites. Bioinformatics (Oxford, England) 102 24413526
1988 Mini-P1 plasmid partitioning: excess ParB protein destabilizes plasmids containing the centromere parS. Journal of bacteriology 100 2962991
1999 Intracellular localization of P1 ParB protein depends on ParA and parS. Proceedings of the National Academy of Sciences of the United States of America 99 10611311
2006 Kallikrein-mediated cell signalling: targeting proteinase-activated receptors (PARs). Biological chemistry 89 16800746
2004 ParB of Pseudomonas aeruginosa: interactions with its partner ParA and its target parS and specific effects on bacterial growth. Journal of bacteriology 83 15466051
2015 Gene Therapy Restores Hair Cell Stereocilia Morphology in Inner Ears of Deaf Whirler Mice. Molecular therapy : the journal of the American Society of Gene Therapy 81 26307667
2011 Intrinsic and integrative properties of substantia nigra pars reticulata neurons. Neuroscience 79 21839148
1997 The evolution of tetrapod ears and the fossil record. Brain, behavior and evolution 77 9310195
1986 Na+ selective channels in the apical membrane of rabbit late proximal tubules (pars recta). Pflugers Archiv : European journal of physiology 70 2421239
2017 Convergence of semantics and emotional expression within the IFG pars orbitalis. NeuroImage 69 28400265
1994 Synaptic connections between pars compacta and pars reticulata neurones: electrophysiological evidence for functional modules within the substantia nigra. Brain research 69 7820690
2011 BARREN STALK FASTIGIATE1 is an AT-hook protein required for the formation of maize ears. The Plant cell 68 21540434
2021 Molecular mechanisms regulating Proteinase-Activated Receptors (PARs). The FEBS journal 65 33742547
2006 Agonists and antagonists of protease activated receptors (PARs). Current medicinal chemistry 61 16475935
2015 Insights into ParB spreading from the complex structure of Spo0J and parS. Proceedings of the National Academy of Sciences of the United States of America 60 25964325
2002 Office-based sutureless transconjunctival pars plana vitrectomy. Retina (Philadelphia, Pa.) 58 12476098
1999 Cell and molecular biology of the pars tuberalis of the pituitary. International review of cytology 58 9750267
2011 Prokaryotic ParA-ParB-parS system links bacterial chromosome segregation with the cell cycle. Plasmid 57 21924286
2006 Proteinase-mediated cell signalling: targeting proteinase-activated receptors (PARs) by kallikreins and more. Biological chemistry 57 16800728
2019 "Ears of the Lynx" MRI Sign Is Associated with SPG11 and SPG15 Hereditary Spastic Paraplegia. AJNR. American journal of neuroradiology 55 30606727
2018 The Effortless Assessment of Risk States (EARS) Tool: An Interpersonal Approach to Mobile Sensing. JMIR mental health 55 30154072
2020 Building inner ears: recent advances and future challenges for in vitro organoid systems. Cell death and differentiation 54 33318601
2008 The contribution of PARs to inflammation and immunity to fungi. Mucosal immunology 54 19079173
2011 Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y-chromosome microdeletions. The Journal of clinical endocrinology and metabolism 51 21252244
2007 Does a melatonin-dependent circadian oscillator in the pars tuberalis drive prolactin seasonal rhythmicity? Journal of neuroendocrinology 51 17620107
1992 The pars tuberalis of the hypophysis: a modulator of the pars distalis? Acta endocrinologica 50 1317627
2021 Relief of ParB autoinhibition by parS DNA catalysis and recycling of ParB by CTP hydrolysis promote bacterial centromere assembly. Science advances 46 34613769
2017 Microbiomes of the normal middle ear and ears with chronic otitis media. The Laryngoscope 46 28397271
2009 Supporting cell characteristics in long-deafened aged mouse ears. Journal of the Association for Research in Otolaryngology : JARO 46 19644644
2021 CTP promotes efficient ParB-dependent DNA condensation by facilitating one-dimensional diffusion from parS. eLife 45 34250901
2002 Analysis of spiral ganglion cell populations in children with normal and pathological ears. The Annals of otology, rhinology, and laryngology 42 12498365
2004 Expression of protease-activated receptors (PARs) in OLN-93 oligodendroglial cells and mechanism of PAR-1-induced calcium signaling. Neuroscience 41 15145074
2014 The eyes and ears are visual indicators of attention in domestic horses. Current biology : CB 39 25093554
2005 Physiology and pathophysiology of proteinase-activated receptors (PARs): role of tryptase/PAR-2 in vascular endothelial barrier function. Journal of pharmacological sciences 39 15655299
2008 Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs). Biological chemistry 38 18627286
2003 The pattern of expression of protease-activated receptors (PARs) during early trophoblast development. The Journal of pathology 38 12692840
2003 Proteinase-mediated signaling: proteinase-activated receptors (PARs) and much more. Life sciences 38 14607251
2010 TNF increases expression of IL-4 and PARs in mast cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 20798517
2005 Physiology and pathophysiology of proteinase-activated receptors (PARs): PAR-2 as a potential therapeutic target. Journal of pharmacological sciences 37 15655295
2015 Lamellar pathology in horses with pituitary pars intermedia dysfunction. Equine veterinary journal 36 25869529
2007 Pressure difference receiving ears. Bioinspiration & biomimetics 35 18364558
2011 Mature middle and inner ears express Chd7 and exhibit distinctive pathologies in a mouse model of CHARGE syndrome. Hearing research 34 21875659
2003 Evidence for surviving outer hair cell function in congenitally deaf ears. The Laryngoscope 32 14603069
2013 Saving ears and kidneys from cisplatin. Anticancer research 30 24122981
2000 BCL-2 protects peroxynitrite-treated thymocytes from poly(ADP-ribose) synthase (PARS)-independent apoptotic but not from PARS-mediated necrotic cell death. Free radical biology & medicine 30 11053771
2009 Ganglion cell and 'dendrite' populations in electric acoustic stimulation ears. Advances in oto-rhino-laryngology 29 19955718
2005 Physiology and pathophysiology of proteinase-activated receptors (PARs): PAR-2-mediated proliferation of colon cancer cell. Journal of pharmacological sciences 28 15655297
2002 Successful allotransplantation of cryopreserved tracheal grafts with preservation of the pars membranacea in nonhuman primates. The Journal of thoracic and cardiovascular surgery 27 11782769
2001 Sciaenid inner ears: a study in diversity. Brain, behavior and evolution 27 11910172
2015 The ParB-parS Chromosome Segregation System Modulates Competence Development in Streptococcus pneumoniae. mBio 26 26126852
2010 The hypophysial pars tuberalis transduces photoperiodic signals via multiple pathways and messenger molecules. General and comparative endocrinology 26 21078321
1999 A replication-incompetent adenovirus vector with the preterminal protein gene deleted efficiently transduces mouse ears. Journal of virology 26 9882305
2000 Expression of EphA4 in developing inner ears of the mouse and guinea pig. Hearing research 25 10601711
2003 Sensitization: a mechanism for melatonin action in the pars tuberalis. Journal of neuroendocrinology 24 12622843
1980 Acute leukemic infiltration of the vitreous diagnosed by pars plana aspiration. American journal of ophthalmology 24 6932819
2007 What have lizard ears taught us about auditory physiology? Hearing research 23 17983712
1995 The substantia nigra pars reticulata, seizures and Fos expression. Epilepsy research 23 7713058
2022 Priority screening of contaminant of emerging concern (CECs) in surface water from drinking water sources in the lower reaches of the Yangtze River based on exposure-activity ratios (EARs). The Science of the total environment 22 36162578
2008 Proteinase-activated receptors (PARs) in infection and inflammation in the gut. The international journal of biochemistry & cell biology 22 18313348
2006 Characterization of the Soj/Spo0J chromosome segregation proteins and identification of putative parS sequences in Helicobacter pylori. Biochemical and biophysical research communications 22 16494844
1994 The human EPRS locus (formerly the QARS locus): a gene encoding a class I and a class II aminoacyl-tRNA synthetase. Genomics 22 8188258
1992 Place-specific derived cochlear microphonics from human ears. Scandinavian audiology 22 1439498
2008 Otoacoustic emissions from insect ears: evidence of active hearing? Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology 21 18516607
1996 Differential regulation of proopiomelanocortin messenger ribonucleic acid in the pars distalis and pars intermedia of the pituitary gland after prolonged hypoxemia in fetal sheep. Endocrinology 21 8770892
2020 Scar-reducing effects of gambogenic acid on skin wounds in rabbit ears. International immunopharmacology 20 33246825
2018 Dysregulation of Cortisol Metabolism in Equine Pituitary Pars Intermedia Dysfunction. Endocrinology 19 30289445
2012 Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14. Biological chemistry 19 22505524
2011 Encoding and decoding photoperiod in the mammalian pars tuberalis. Neuroendocrinology 18 21778697
2010 Hes1 regulates formations of the hypophyseal pars tuberalis and the hypothalamus. Cell and tissue research 18 20431921
2004 Shooting for PARs in lung diseases. Current opinion in pharmacology 18 15140412
1999 Ventromedial focus of cell death is absent during development of Xenopus and zebrafish inner ears. Journal of neurocytology 18 10900084
2019 Triggering of protease-activated receptors (PARs) induces alternative M2 macrophage polarization with impaired plasticity. Molecular immunology 17 31419704
2013 Negative regulation of neuromedin U mRNA expression in the rat pars tuberalis by melatonin. PloS one 17 23843987
2013 Multiple indices of the 'bounce' phenomenon obtained from the same human ears. Journal of the Association for Research in Otolaryngology : JARO 17 24253659
2012 Distinct neurogenic potential in the retinal margin and the pars plana of mammalian eye. The Journal of neuroscience : the official journal of the Society for Neuroscience 17 22973003
2009 Modulation of expression of innate immunity markers CXCL5/ENA-78 and CCL20/MIP3alpha by protease-activated receptors (PARs) in human gingival epithelial cells. Innate immunity 17 19567485
1990 Different tympanometric procedures compared with direct pressure measurements in healthy ears. Scandinavian audiology 17 2237258
1979 Intercellular junctions in the rhesus monkey pars distalis. The Anatomical record 17 115336
2023 Targeting Transient Receptor Potential (TRP) Channels, Mas-Related G-Protein-Coupled Receptors (Mrgprs), and Protease-Activated Receptors (PARs) to Relieve Itch. Pharmaceuticals (Basel, Switzerland) 16 38139833
2015 Protease-activated receptors (PARs) in cancer: Novel biased signaling and targets for therapy. Methods in cell biology 16 26928551
2014 "Platelet-associated regulatory system (PARS)" with particular reference to female reproduction. Journal of ovarian research 16 24883111
2012 Proteinase-activated receptors (PARs) and calcium signaling in cancer. Advances in experimental medicine and biology 16 22453980
2000 Sequencing and characterization of the cryptic plasmid QpRS from Coxiella burnetii. Plasmid 16 10873529