Affinage

EIF2S3

Eukaryotic translation initiation factor 2 subunit 3 · UniProt P41091

Round 2 corrected
Length
472 aa
Mass
51.1 kDa
Annotated
2026-04-28
130 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2S3 encodes eIF2γ, the central GTPase subunit of the heterotrimeric eIF2 complex that delivers Met-tRNAiMet to the 40S ribosomal subunit during translation initiation. eIF2γ binds GTP and the acceptor stem of Met-tRNAi directly, while its domain III contacts 18S rRNA helix h44 on the ribosome rather than tRNA, distinguishing it functionally from the structurally related elongation factor EF-Tu (PMID:15788752, PMID:22002225). The β subunit of eIF2 binds eIF2γ through a ~78-residue C-terminal region, and proper eIF2 heterotrimer assembly requires the dedicated assembly factor CDC123, which engages the unassembled γ subunit via its domain III (PMID:10769173, PMID:23775072). Loss-of-function mutations in EIF2S3 cause MEHMO syndrome (intellectual disability, epilepsy, hypogonadism, microcephaly, obesity) by disrupting eIF2 complex integrity, reducing ternary complex levels, and dysregulating the integrated stress response—defects partially rescued by the eIF2B activator ISRIB (PMID:23063529, PMID:28055140, PMID:31836389).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1986 Medium

    Direct protein sequencing established the identity of the eIF2γ polypeptide, enabling subsequent molecular and genetic studies of this subunit.

    Evidence Reversed-phase HPLC isolation and N-terminal sequencing of rabbit reticulocyte eIF2γ

    PMID:3745199

    Open questions at the time
    • Only partial N-terminal sequence obtained; full-length primary structure not yet determined
  2. 1998 High

    Mapping EIF2S3 to the X chromosome at Xp21 and showing it escapes X-inactivation established its unusual dosage biology and set the stage for understanding X-linked disease associations.

    Evidence Chromosomal mapping, Northern blot, and cross-species genomic analysis

    PMID:9736774

    Open questions at the time
    • Functional consequences of X-inactivation escape on eIF2γ dosage not tested
  3. 2000 Medium

    Domain mapping revealed that eIF2β binds eIF2γ directly through ~78 C-terminal residues, establishing the subunit interaction architecture of the eIF2 complex.

    Evidence Comparative sequence analysis and in vitro binding assays between eIF2β fragments and eIF2γ

    PMID:10769173

    Open questions at the time
    • Structural basis of the β–γ interface not resolved at atomic level
    • Contribution of eIF2α to complex stability not addressed
  4. 2005 High

    Reconstitution of the archaeal eIF2 heterotrimer demonstrated that the γ subunit is the principal GTP- and Met-tRNAi-binding subunit, delineating its biochemical activities from those of the α and β subunits.

    Evidence Recombinant protein reconstitution with in vitro GTP/GDP and Met-tRNAi binding assays using Sulfolobus solfataricus a/eIF2

    PMID:15788752

    Open questions at the time
    • Eukaryotic-specific regulatory inputs (e.g., phospho-eIF2α) not recapitulated in archaeal system
  5. 2011 High

    Hydroxyl radical probing resolved how eIF2γ engages both tRNA and the ribosome: its acceptor-stem-binding surface contacts Met-tRNAi, while domain III contacts 18S rRNA helix h44, revealing a ribosome-binding role distinct from the tRNA-binding function of the analogous EF-Tu domain III.

    Evidence Directed hydroxyl radical probing (Fe-BABE), mutagenesis, and ribosome/tRNA binding assays in S. cerevisiae

    PMID:22002225

    Open questions at the time
    • High-resolution cryo-EM or crystal structure of eukaryotic eIF2γ on the 40S not yet available at this time
    • Dynamics of domain III conformational changes during scanning not addressed
  6. 2012 High

    Discovery that a missense EIF2S3 mutation causes X-linked intellectual disability with microcephaly linked eIF2γ to human neurodevelopmental disease and showed the mutation disrupts eIF2β–γ binding and start codon selection.

    Evidence Exome sequencing, co-immunoprecipitation in human cells, yeast start codon selection assays with genetic suppression by eIF2β overexpression

    PMID:23063529

    Open questions at the time
    • Whether the mutation affects GTP hydrolysis or ternary complex formation specifically was not determined
    • Brain-specific consequences not modeled
  7. 2013 High

    Identification of CDC123 as a dedicated eIF2 assembly factor that binds unassembled eIF2γ through domain III revealed a previously unknown biogenesis step required for eIF2 heterotrimer formation.

    Evidence Yeast genetics, co-immunoprecipitation, polysome profiling, GCN4 reporter, domain mapping, and genetic rescue of cdc123Δ

    PMID:23775072

    Open questions at the time
    • Mechanism by which CDC123 promotes assembly (chaperone vs. scaffold) not resolved
    • Whether mammalian CDC123 (D123) functions identically not confirmed in mammalian cells at this time
  8. 2017 High

    Establishing that the EIF2S3 Ile465Serfs frameshift causes MEHMO syndrome with ISR activation in patient fibroblasts, and correlating mutation severity with clinical severity via yeast assays, defined the genotype–phenotype relationship for EIF2S3 loss-of-function alleles.

    Evidence Patient fibroblast ISR markers (phospho-eIF2α, ATF4), yeast complementation comparing frameshift vs. missense alleles

    PMID:28055140

    Open questions at the time
    • Neuronal cell-type-specific vulnerability mechanisms not addressed
    • Contribution of ISR hyperactivation vs. global translation reduction to pathology unclear
  9. 2019 High

    Patient-derived iPSC studies showed that the MEHMO frameshift mutation impairs CDC123-mediated eIF2 assembly and reduces ternary complex levels, and that the eIF2B activator ISRIB rescues translation, growth, and neuronal differentiation defects, identifying a potential therapeutic strategy.

    Evidence Patient iPSCs with ternary complex measurement, polysome profiling, eIF2 Co-IP, neuronal differentiation, and ISRIB pharmacological rescue

    PMID:31836389

    Open questions at the time
    • In vivo efficacy of ISRIB in animal models of MEHMO not tested
    • Whether ISRIB rescue is sustained long-term or affects all MEHMO-relevant tissues unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • High-resolution structural data for the eukaryotic eIF2γ in context of the full eIF2–tRNA–ribosome complex, the precise mechanism by which CDC123 promotes γ-subunit assembly, and whether ISRIB or related ISR modulators can rescue neurodevelopmental deficits in vivo remain unresolved.
  • Atomic-resolution structure of mammalian eIF2γ in ribosomal context
  • Mechanism of CDC123-mediated assembly not defined biochemically
  • In vivo therapeutic rescue of MEHMO phenotypes not demonstrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 4 GO:0003723 RNA binding 2 GO:0003924 GTPase activity 2
Localization
GO:0005829 cytosol 2 GO:0005840 ribosome 1
Pathway
R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 1
Partners
CDC123EIF2S1EIF2S2
Complex memberships
eIF2 (eIF2α–eIF2β–eIF2γ heterotrimer)eIF2 ternary complex (eIF2–GTP–Met-tRNAi)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1986 The NH2-terminal amino acid sequence of the γ subunit of rabbit reticulocyte eIF2 was determined by direct sequencing of the protein isolated by reversed-phase HPLC after resolution of eIF2 subunits. Reversed-phase HPLC subunit isolation, direct protein sequencing The Journal of biological chemistry Medium 3745199
1998 The gene encoding eIF2γ (EIF2S3) is located on the human X chromosome at Xp21 and escapes X-inactivation. In mice, both X and Y chromosome homologues exist (with 98% amino acid identity), but humans lack a Y copy. Autosomal retroposons of eIF2γ exist in both humans and mice. Chromosomal mapping, Northern blot, sequence analysis, Ark blot analysis of eutherian and metatherian genomic DNA Human molecular genetics High 9736774
1998 eIF2γ is evolutionarily most closely related to SELB (the selenocysteine-specific elongation factor from eubacteria) within the GTPase superfamily, and the archaeal/eukaryotic eIF2γ proteins form a distinct ancient subfamily of GTPases that diverged prior to the last common ancestor of extant life. Phylogenetic sequence analysis of eIF2γ gene fragments from diplomonads, parabasalia, microsporidia, and archaebacteria Journal of molecular evolution Medium 9847405
2000 eIF2γ (encoded by EIF2S3) was identified as a required cofactor for hepatitis C virus (HCV) IRES-mediated translation. Ribozymes targeting eIF2γ mRNA specifically inhibited HCV IRES-driven translation of core protein without affecting cap-dependent translation or cell growth. Functional genomics hairpin ribozyme library selection, ribozyme validation of HCV IRES translation inhibition, cap-dependent translation controls Proceedings of the National Academy of Sciences of the United States of America Medium 10900014
2000 The sequence of eIF2β homologous to archaeal aIF2β (approximately 78 C-terminal residues) is sufficient for binding eIF2γ, establishing that eIF2γ is the only eIF2 subunit with which eIF2β directly interacts. eIF5, despite sequence similarity to eIF2β, does not interact with eIF2γ due to a gap in homology in this region. Comparative sequence analysis, in vitro binding/interaction assays between eIF2β and eIF2γ subunits The Biochemical journal Medium 10769173
2004 Cdc123 (homolog of mammalian D123) controls cell division by regulating the abundance of Gcd11 (eIF2γ, the yeast ortholog of EIF2S3). Loss of cdc123 function depletes Gcd11 protein levels and causes G1 arrest; Gcd11 overexpression can rescue cdc123 defects, placing Cdc123 upstream of eIF2γ in a pathway controlling cell cycle entry. Yeast genetics (cdc123 mutant analysis), cell cycle staging, protein abundance measurement, genetic suppression/rescue experiments The Journal of biological chemistry Medium 15319434
2004 The γ subunit of eIF2 (eIF2γ) confers both tRNA and GTP/GDP binding activities to the eIF2 complex, and is the most conserved subunit across eukaryotes. Phylogenetic analysis of eIF2γ intron positions demonstrates that it is a suitable marker for eukaryotic evolution, with conserved ancient intron positions. Phylogenetic sequence analysis, intron position mapping across 55 eIF2γ genes from 13 arthropod species and diverse eukaryotes Molecular biology and evolution Low 15356279
2005 The archaeal homologue of eIF2 (a/eIF2) reconstituted from recombinant subunits of Sulfolobus solfataricus shows that the trimeric factor interacts with GTP and Met-tRNAi and stimulates binding of initiator tRNA to the small ribosomal subunit. Unlike eukaryotic eIF2, a/eIF2 has similar affinities for GDP and GTP, and the β-subunit does not contribute to tRNAi binding—demonstrating that the γ subunit is the primary tRNA- and GTP-binding subunit. Recombinant protein reconstitution, in vitro GTP/GDP binding assays, Met-tRNAi binding assays, ribosomal subunit binding assays Nucleic acids research High 15788752
2011 Directed hydroxyl radical probing experiments in S. cerevisiae revealed that eIF2γ primarily contacts the acceptor stem of Met-tRNAi(Met) and that domain III of eIF2γ forms a key binding interface with 18S rRNA helix h44 on the 40S ribosomal subunit. Unlike the structurally analogous domain III of EF-Tu (which contacts the T stem of tRNA), eIF2γ domain III functions in ribosome binding rather than tRNA binding. Directed hydroxyl radical probing (Fe-BABE tethered cleavage), biochemical mutational analysis of eIF2γ domain III, ribosome binding assays, Met-tRNAi binding assays Nature structural & molecular biology High 22002225
2012 A missense mutation in EIF2S3 (encoding eIF2γ) causes an X-chromosomal neurological syndrome characterized by intellectual disability and microcephaly. Biochemical studies showed the mutation disrupts binding of the eIF2β subunit to eIF2γ, impairing eIF2 complex integrity. In yeast with the analogous eIF2γ mutation, translation start codon selection was impaired, and the defect was suppressed by overexpressing eIF2β. Human genetics (exome sequencing), overexpression of mutant eIF2γ in human cells (co-immunoprecipitation of subunits), yeast model with analogous mutation (start codon selection assay, genetic suppression by eIF2β overexpression) Molecular cell High 23063529
2013 Cdc123 functions as a dedicated eIF2 assembly factor that binds the unassembled eIF2γ subunit (but not the assembled eIF2 complex) through the C-terminal domain III region of eIF2γ. Mutations in CDC123 reduce association of eIF2 subunits, decrease polysome levels, and increase GCN4 expression. High levels of Cdc123 can neutralize eIF2γ assembly defects, and co-overexpression of all three eIF2 subunits rescues an otherwise lethal cdc123 deletion. Yeast genetics (CDC123 mutations, deletion), co-immunoprecipitation of eIF2 subunits, polysome profiling, GCN4 expression assay, domain mapping of eIF2γ-Cdc123 interaction, genetic rescue experiments The Journal of biological chemistry High 23775072
2016 Two novel EIF2S3 mutations (missense c.777T>G p.Ile259Met and frameshift c.1394_1397del p.Ile465Serfs*4) cause syndromic intellectual disability with microcephaly, growth retardation, and epilepsy. Morpholino-based knockdown of the zebrafish EIF2S3 ortholog (eif2s3) recapitulates the human microcephaly and short stature phenotype, confirming pathogenicity. X-chromosome exome sequencing, zebrafish morpholino knockdown with morphological phenotyping American journal of medical genetics. Part A Medium 27333055
2017 EIF2S3 frameshift mutation (Ile465Serfs) causes MEHMO syndrome (intellectual disability, epilepsy, hypogonadism, microcephaly, obesity). Patient fibroblasts show increased integrated stress response (ISR) activation. Functional assays in yeast demonstrate the Ile465Serfs mutation impairs eIF2γ function more severely than tested missense mutations, correlating with the more severe clinical phenotype. Clinical genetics, patient fibroblast ISR activation assays (phospho-eIF2α, ATF4 induction), yeast functional complementation assays comparing frameshift vs. missense mutations Human mutation High 28055140
2019 A C-terminal EIF2S3 frameshift mutation (found in MEHMO syndrome patients) impairs CDC123-mediated promotion of eIF2 complex formation and reduces the level of eIF2-GTP-Met-tRNAiMet ternary complexes in patient-derived induced pluripotent stem cells. This reduction in eIF2 activity dysregulates global and gene-specific protein synthesis and enhances cell death upon stress. Treatment with ISRIB (an activator of eIF2B, the guanine nucleotide exchange factor for eIF2) rescues cell growth, translation, and neuronal differentiation defects. Patient-derived iPSCs, ternary complex level measurement, polysome profiling, eIF2 subunit co-immunoprecipitation, neuronal differentiation assay, ISRIB pharmacological rescue Molecular cell High 31836389

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
2006 Coping with stress: eIF2 kinases and translational control. Biochemical Society transactions 1050 16246168
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Nucleolar proteome dynamics. Nature 934 15635413
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
2020 Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science (New York, N.Y.) 653 32680882
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. Journal of proteome research 422 20020773
1995 The histidyl-tRNA synthetase-related sequence in the eIF-2 alpha protein kinase GCN2 interacts with tRNA and is required for activation in response to starvation for different amino acids. Molecular and cellular biology 415 7623840
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2015 Proteome-wide profiling of protein assemblies by cross-linking mass spectrometry. Nature methods 370 26414014
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2011 Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. The Journal of biological chemistry 339 21285359
2011 The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress. Molecular biology of the cell 330 21917591
2004 eIF2 and the control of cell physiology. Seminars in cell & developmental biology 319 15659334
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
1979 Mechanism of interferon action: phosphorylation of protein synthesis initiation factor eIF-2 in interferon-treated human cells by a ribosome-associated kinase processing site specificity similar to hemin-regulated rabbit reticulocyte kinase. Proceedings of the National Academy of Sciences of the United States of America 276 284384
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
1999 Eukaryotic initiation factor eIF2. The international journal of biochemistry & cell biology 270 10216940
2022 EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Molecular cancer 257 35031058
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
1995 Regulation of protein synthesis by heme-regulated eIF-2 alpha kinase. Trends in biochemical sciences 251 7709427
2005 Emergence of young human genes after a burst of retroposition in primates. PLoS biology 248 16201836
1993 Increased expression of eukaryotic translation initiation factors eIF-4E and eIF-2 alpha in response to growth induction by c-myc. Proceedings of the National Academy of Sciences of the United States of America 244 8327497
2008 Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. The Journal of biological chemistry 243 18195013
2010 Endoplasmic reticulum stress response mediated by the PERK-eIF2(alpha)-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. The Journal of biological chemistry 237 21135100
2014 Keeping the eIF2 alpha kinase Gcn2 in check. Biochimica et biophysica acta 235 24732012
2017 Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification. Nature communications 221 28524877
2010 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunology and cell biology 221 20458337
1998 eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes & development 218 9472020
2002 Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation. Cell stress & chaperones 217 12380690
2009 Proteomic analysis of integrin-associated complexes identifies RCC2 as a dual regulator of Rac1 and Arf6. Science signaling 207 19738201
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2010 Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 195 20434207
2004 Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. The Journal of biological chemistry 188 15213227
1989 Purification and activation of the double-stranded RNA-dependent eIF-2 kinase DAI. Molecular and cellular biology 182 2725516
2001 Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis. Progress in molecular and subcellular biology 169 11575161
2001 Translation inhibition in apoptosis: caspase-dependent PKR activation and eIF2-alpha phosphorylation. The Journal of biological chemistry 157 11555640
2020 ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Molecular cell 150 33220178
1995 GCN20, a novel ATP binding cassette protein, and GCN1 reside in a complex that mediates activation of the eIF-2 alpha kinase GCN2 in amino acid-starved cells. The EMBO journal 141 7621831
2019 The structural basis of translational control by eIF2 phosphorylation. Nature communications 134 31086188
1994 The eIF-2 alpha kinases: regulators of protein synthesis in starvation and stress. Seminars in cell biology 127 7711290
1994 eIF-2 kinases: regulators of general and gene-specific translation initiation. Trends in biochemical sciences 127 7855893
2007 HCV and CSFV IRES domain II mediate eIF2 release during 80S ribosome assembly. The EMBO journal 124 17255934
1995 Structural requirements for double-stranded RNA binding, dimerization, and activation of the human eIF-2 alpha kinase DAI in Saccharomyces cerevisiae. Molecular and cellular biology 124 7799945
2009 Genome-wide analysis of tRNA charging and activation of the eIF2 kinase Gcn2p. The Journal of biological chemistry 122 19546227
2012 Eukaryotic initiation factor 2 (eIF2) signaling regulates proinflammatory cytokine expression and bacterial invasion. The Journal of biological chemistry 120 22761422
2021 Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease. Science signaling 110 33531382
1978 Binding and release of eukaryotic initiation factor eIF-2 and GTP during protein synthesis initiation. Proceedings of the National Academy of Sciences of the United States of America 110 272635
2006 Initiation of protein synthesis by hepatitis C virus is refractory to reduced eIF2.GTP.Met-tRNA(i)(Met) ternary complex availability. Molecular biology of the cell 109 16928960
1996 Histidyl-tRNA synthetase-related sequences in GCN2 protein kinase regulate in vitro phosphorylation of eIF-2. The Journal of biological chemistry 103 8798780
2014 Selective mRNA translation during eIF2 phosphorylation induces expression of IBTKα. Molecular biology of the cell 98 24648495
1980 Characterization of double-stranded-RNA-activated kinase that phosphorylates alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha) in reticulocyte lysates. Proceedings of the National Academy of Sciences of the United States of America 92 6928683
1992 Truncated protein phosphatase GLC7 restores translational activation of GCN4 expression in yeast mutants defective for the eIF-2 alpha kinase GCN2. Molecular and cellular biology 91 1333044
2010 eIF5 has GDI activity necessary for translational control by eIF2 phosphorylation. Nature 85 20485439
2004 Differential activation of eIF2 kinases in response to cellular stresses in Schizosaccharomyces pombe. Genetics 82 15611163
2014 ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PloS one 80 24594939
1998 Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution. Human molecular genetics 78 9736774
2018 Noncanonical Modulation of the eIF2 Pathway Controls an Increase in Local Translation during Neural Wiring. Molecular cell 75 30595434
2006 Age-specific CUGBP1-eIF2 complex increases translation of CCAAT/enhancer-binding protein beta in old liver. The Journal of biological chemistry 75 16931514
2000 Identification of eIF2Bgamma and eIF2gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach. Proceedings of the National Academy of Sciences of the United States of America 75 10900014
2007 PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC cell biology 74 17727724
2004 Parasite-specific eIF2 (eukaryotic initiation factor-2) kinase required for stress-induced translation control. The Biochemical journal 73 14989696
2012 eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Molecular cell 71 23063529
1998 Inhibition of protein synthesis by nitric oxide correlates with cytostatic activity: nitric oxide induces phosphorylation of initiation factor eIF-2 alpha. Molecular medicine (Cambridge, Mass.) 68 9562976
1989 Disulfide bond formation in the regulation of eIF-2 alpha kinase by heme. The Journal of biological chemistry 67 2722851
2013 eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation. Genes & development 64 24352424
1994 Erythroid expression of the heme-regulated eIF-2 alpha kinase. Molecular and cellular biology 60 7910943
1994 Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs. Biochimie 59 7534482
1991 Eukaryotic initiation factors eIF-2 and eIF-3: interactions, structure and localization in ribosomal initiation complexes. Biochimie 58 1742346
2017 EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. Human mutation 56 28055140
2011 SIRT1 associates with eIF2-alpha and regulates the cellular stress response. Scientific reports 56 22355666
2005 The archaeal eIF2 homologue: functional properties of an ancient translation initiation factor. Nucleic acids research 56 15788752
1994 Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression. The Journal of biological chemistry 56 7908290
2014 Human eukaryotic initiation factor 2 (eIF2)-GTP-Met-tRNAi ternary complex and eIF3 stabilize the 43 S preinitiation complex. The Journal of biological chemistry 54 25246524
1981 Cross-linking of Met-tRNAf to eIF-2 beta and to the ribosomal proteins S3a and S6 within the eukaryotic inhibition complex, eIF-2 .GMPPCP.Met-tRNAf.small ribosomal subunit. Nucleic acids research 54 6910637
2020 A Retrospective on eIF2A-and Not the Alpha Subunit of eIF2. International journal of molecular sciences 51 32192132
2020 Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection. Stem cell reports 51 32220329
2005 Dynamic cycling of eIF2 through a large eIF2B-containing cytoplasmic body: implications for translation control. The Journal of cell biology 51 16157703
2011 Initiation factor eIF2γ promotes eIF2-GTP-Met-tRNAi(Met) ternary complex binding to the 40S ribosome. Nature structural & molecular biology 50 22002225
2009 Control of HIF-1alpha expression by eIF2 alpha phosphorylation-mediated translational repression. Cancer research 50 19244104
1979 The activity of eukaryotic initiation factor eIF-2 in ternary complex formation with GTP and Met-tRNA. The Journal of biological chemistry 50 429345
2022 GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis. eLife 49 36107759
2010 The eIF2 kinase GCN2 is essential for the murine immune system to adapt to amino acid deprivation by asparaginase. The Journal of nutrition 49 20861212
1991 Tissue distribution and immunoreactivity of heme-regulated eIF-2 alpha kinase determined by monoclonal antibodies. Biochemistry 49 1672093
1989 Association of mRNA and eIF-2 alpha with the cytoskeleton in cells lacking vimentin. Experimental cell research 49 2466674
2013 Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease. Neurobiology of disease 48 24269915
2011 Methods for analyzing eIF2 kinases and translational control in the unfolded protein response. Methods in enzymology 48 21266259
1990 Increased eIF-2 alpha expression in mitogen-activated primary T lymphocytes. The EMBO journal 47 1701139
1991 Activation of the double-stranded RNA-dependent eIF-2 alpha kinase by cellular RNA from 3T3-F442A cells. European journal of biochemistry 46 1703958
1994 Endogenous inhibitors of the dsRNA-dependent eIF-2 alpha protein kinase PKR in normal and ras-transformed cells. Biochimie 45 7893828
2008 The regulatory beta subunit of protein kinase CK2 contributes to the recognition of the substrate consensus sequence. A study with an eIF2 beta-derived peptide. Biochemistry 44 18636746
2004 Cdc123 and checkpoint forkhead associated with RING proteins control the cell cycle by controlling eIF2gamma abundance. The Journal of biological chemistry 44 15319434
1998 Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B. The Journal of biological chemistry 44 9446619
2016 Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. American journal of medical genetics. Part A 42 27333055
2007 Double stranded RNA activated EIF2 alpha kinase (EIF2AK2; PKR) is associated with Alzheimer's disease. Neurobiology of aging 42 17420072
2019 PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells. Cell death & disease 41 31395860
2017 The eIF2-alpha kinase HRI: a potential target beyond the red blood cell. Expert opinion on therapeutic targets 40 29063813
2020 Inhibition of the integrated stress response by viral proteins that block p-eIF2-eIF2B association. Nature microbiology 38 32690955
2019 Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB. Molecular cell 38 31836389
2015 OLA1 regulates protein synthesis and integrated stress response by inhibiting eIF2 ternary complex formation. Scientific reports 38 26283179
2004 Phylogenetic mapping of intron positions: a case study of translation initiation factor eIF2gamma. Molecular biology and evolution 38 15356279
2024 Multiple mechanisms activate GCN2 eIF2 kinase in response to diverse stress conditions. Nucleic acids research 37 38281137
2021 Discordant regulation of eIF2 kinase GCN2 and mTORC1 during nutrient stress. Nucleic acids research 37 34023907
1989 Serum growth factors cause rapid stimulation of protein synthesis and dephosphorylation of eIF-2 in serum deprived Ehrlich cells. Biochimica et biophysica acta 36 2605256
1998 Evolutionary relationship between translation initiation factor eIF-2gamma and selenocysteine-specific elongation factor SELB: change of function in translation factors. Journal of molecular evolution 35 9847405
1986 The NH2-terminal sequence of the alpha and gamma subunits of eukaryotic initiation factor 2 and the phosphorylation site for the heme-regulated eIF-2 alpha kinase. The Journal of biological chemistry 35 3745199
2016 Perturbations in actin dynamics reconfigure protein complexes that modulate GCN2 activity and promote an eIF2 response. Journal of cell science 34 27852836
2001 Protection of translation initiation factor eIF2 phosphorylation correlates with eIF2-associated glycoprotein p67 levels and requires the lysine-rich domain I of p67. Biochimie 33 11728629
2000 Conserved sequences in the beta subunit of archaeal and eukaryal translation initiation factor 2 (eIF2), absent from eIF5, mediate interaction with eIF2gamma. The Biochemical journal 33 10769173
2021 eIF2-dependent translation initiation: Memory consolidation and disruption in Alzheimer's disease. Seminars in cell & developmental biology 32 34304995
2013 Translation initiation requires cell division cycle 123 (Cdc123) to facilitate biogenesis of the eukaryotic initiation factor 2 (eIF2). The Journal of biological chemistry 32 23775072
2011 Gcn1 and actin binding to Yih1: implications for activation of the eIF2 kinase GCN2. The Journal of biological chemistry 32 21239490
2008 The PERK/eIF2 alpha signaling pathway of Unfolded Protein Response is essential for N-(4-hydroxyphenyl)retinamide (4HPR)-induced cytotoxicity in cancer cells. Experimental cell research 32 18342855
1998 The phosphorylation state of the wheat translation initiation factors eIF4B, eIF4A, and eIF2 is differentially regulated during seed development and germination. The Journal of biological chemistry 32 9685349
1979 Protein synthesis in rabbit reticulocytes: characteristics of a postribosomal supernatant factor that reverses inhibition of protein synthesis in heme-deficient lysates and inhibition of ternary complex (Met-tRNAfMet.eIF-2.GTP) formation by heme-regulated inhibitor. Proceedings of the National Academy of Sciences of the United States of America 31 293657
1981 Protein synthesis in brine shrimp embryos. Regulation of the formation of the ternary complex (Met-tRNAf X eIF-2 X GTP) by two purified protein factors and phosphorylation of Artemia eIF-2. European journal of biochemistry 30 6912815
2013 Evolutionarily conserved IMPACT impairs various stress responses that require GCN1 for activating the eIF2 kinase GCN2. Biochemical and biophysical research communications 29 24333428
2012 Requirements for eIF4A and eIF2 during translation of Sindbis virus subgenomic mRNA in vertebrate and invertebrate host cells. Cellular microbiology 29 23189929
2020 Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway. Nutrients 28 33302552