Affinage

EIF2B4

Translation initiation factor eIF2B subunit delta · UniProt Q9UI10

Length
523 aa
Mass
57.6 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2B4 encodes the δ-subunit of eIF2B, the essential heterodecameric guanine nucleotide exchange factor (GEF) that catalyzes GDP-to-GTP exchange on eIF2 to sustain translation initiation. Within the decamer (a dimer of αβγδε pentamers), the δ-subunit is a core component of the regulatory subcomplex (α/β/δ) that senses phosphorylated eIF2α(P) and transmits inhibitory signals to the catalytic γ/ε subcomplex; a point mutation in the δ-subunit can render eIF2B insensitive to eIF2α phosphorylation, and an alternative δ-subunit isoform (V1) uncouples eIF2B from the integrated stress response by abolishing eIF2 interaction (PMID:9582312, PMID:20709751). The δ-subunit is pivotal for βγδε tetramer formation and contributes to the binding pocket of ISRIB, a small molecule that stabilizes the decameric assembly and restores GEF activity in Vanishing White Matter (VWM) disease mutants (PMID:24532666, PMID:25875391, PMID:29489452). Mutations in EIF2B4, along with those in other eIF2B subunit genes, cause VWM disease by destabilizing the decameric holoenzyme and impairing nucleotide exchange (PMID:29489452).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1993 High

    Identifying how growth-factor signaling reaches the translational machinery, GSK-3 was shown to phosphorylate eIF2Bε and to be rapidly inactivated by insulin, establishing the first kinase-mediated regulatory input into eIF2B.

    Evidence Kinase activity assay with chromatographic fractions and phosphatase-2A reversal in cell extracts

    PMID:8397507

    Open questions at the time
    • Phosphorylation site on eIF2Bε not yet identified
    • Direct role of the δ-subunit in this regulation unknown
  2. 1998 High

    Defining eIF2B's subunit architecture and functional division, the complex was resolved into a regulatory subcomplex (α/β/δ) that binds eIF2α(P) without exchange activity, and a catalytic subcomplex (γ/ε) that performs nucleotide exchange but is insensitive to phosphorylation; a δ-subunit mutation was shown to confer insensitivity to eIF2α(P), directly implicating the δ-subunit in phospho-regulation.

    Evidence Reconstituted in vitro GEF assays with purified recombinant subcomplexes, baculovirus-expressed deletion complexes, yeast genetic suppressor analysis

    PMID:8887689 PMID:9472020 PMID:9582312

    Open questions at the time
    • Structural basis for δ-subunit's role in phospho-sensing unresolved
    • Stoichiometry of the holoenzyme not yet established
  3. 2001 High

    Mapping the eIF2–eIF2B interaction surface revealed that the δ- and ε-subunits of eIF2B directly contact eIF2, while phosphorylated eIF2α binds the regulatory subcomplex in a phosphorylation-stimulated manner; binding of eIF2α(P) is required for inhibition of GEF activity.

    Evidence Far-Western blots of individual subunits, GST pulldown with phosphorylated eIF2α, genetic suppressor analysis

    PMID:11438658 PMID:9446619

    Open questions at the time
    • Atomic-resolution contacts between δ-subunit and eIF2 unknown
    • How phospho-eIF2α binding to regulatory subcomplex blocks catalytic subcomplex action is unclear
  4. 2005 High

    Demonstrating spatial organization of GEF activity in vivo, eIF2B was found to reside in dedicated cytoplasmic foci where eIF2 dynamically shuttles for nucleotide exchange; disrupting eIF2B function by three independent strategies blocked eIF2 cycling into these foci.

    Evidence Live fluorescence co-localization and FRAP in yeast with genetic/pharmacological perturbations

    PMID:16157703

    Open questions at the time
    • Whether mammalian eIF2B forms analogous exchange bodies unknown
    • Role of individual subunits in body formation unresolved
  5. 2010 Medium

    An alternative δ-subunit isoform (V1) was discovered to uncouple eIF2B from the integrated stress response: cells expressing only V1 showed no eIF2α phosphorylation–dependent translational suppression and no ATF4 induction, because V1 cannot interact with eIF2.

    Evidence Isoform-specific expression in cancer cell lines, eIF2B–eIF2 interaction assays, ATF4 reporter and translation assays

    PMID:20709751

    Open questions at the time
    • Structural basis for V1's inability to bind eIF2 not determined
    • Physiological contexts where V1 predominates unclear
    • Single-lab observation without independent replication
  6. 2014 High

    Resolving a longstanding stoichiometric question, native mass spectrometry established that eIF2B is a decamer (dimer of pentamers), with the δ-subunit pivotal for βγδε tetramer formation; decameric assemblies showed greater eIF2 binding and GEF activity than tetramers.

    Evidence Native MS, chemical cross-linking, co-immunoprecipitation of overexpressed subunit-deletion complexes

    PMID:24532666 PMID:24852487

    Open questions at the time
    • High-resolution structure of complete decamer not yet available
    • How δ-subunit drives tetramer formation at atomic level unresolved
  7. 2015 High

    Identifying the drug target explaining ISRIB's mechanism, the δ-subunit was shown to contribute to the ISRIB-binding pocket; ISRIB stabilizes decameric assembly and overcomes eIF2α phosphorylation-mediated translational inhibition. Crystal structure of the regulatory subcomplex revealed that β and δ form a (βδ)₂ tetramer related to sugar isomerases.

    Evidence shRNA screen, ISRIB analog SAR, X-ray crystallography of eIF2B regulatory subcomplex, mutational analysis

    PMID:25875391 PMID:26384431

    Open questions at the time
    • Precise atomic contacts between ISRIB and δ-subunit residues not yet mapped
    • Whether ISRIB acts identically in all cell types unknown
  8. 2018 High

    Linking eIF2B biochemistry to human disease, VWM disease mutations across eIF2B subunits (including EIF2B4/δ) were shown to destabilize the decamer and reduce GEF activity; ISRIB could stabilize mutant decamers and partially restore catalytic function.

    Evidence GEF activity and stability assays of recombinant VWM mutant eIF2B complexes, cell-based ISR activation assays

    PMID:29489452

    Open questions at the time
    • In vivo efficacy of ISRIB for VWM disease not established
    • Mutation-specific effects on δ-subunit folding or intersubunit contacts uncharacterized
  9. 2019 High

    Cryo-EM structures of eIF2B with unphosphorylated and phosphorylated eIF2 revealed two completely different binding modes: productive (exchange-active) versus nonproductive (inhibitory), with phosphorylation-induced refolding of eIF2α creating a new interface that sequesters eIF2B.

    Evidence Cryo-EM and X-ray crystallography of eIF2B–eIF2 complexes in both phosphorylation states

    PMID:31048491 PMID:31048492

    Open questions at the time
    • Dynamic transitions between productive and nonproductive modes not captured
    • Contribution of individual δ-subunit residues to either binding mode not dissected
  10. 2021 High

    Integrating assembly, allostery, and metabolic sensing, studies showed that eIF2B assembly state itself regulates the ISR (tetramers activate ISR), ISRIB antagonizes eIF2α(P) through allosteric rocking of the decamer, and sugar phosphates bind the α-subunit to promote holoenzyme formation and enhance GEF activity.

    Evidence Cryo-EM of assembly intermediates, X-ray crystallography of sugar phosphate–bound eIF2B, in vitro activity screens, ISR reporter assays, VWM mutant analysis

    PMID:33688831 PMID:34103529

    Open questions at the time
    • Physiological sugar phosphate concentrations that regulate eIF2B in vivo uncharacterized
    • Whether δ-subunit conformational changes contribute to the rocking mechanism remains undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The precise structural determinants within the δ-subunit that drive tetramer nucleation, the atomic contacts mediating ISRIB binding to δ-subunit residues, and the structural basis for V1 isoform dysfunction remain undefined.
  • High-resolution structure of ISRIB bound specifically at δ-subunit interface needed
  • Isoform-specific structural comparisons lacking
  • In vivo therapeutic relevance of ISRIB for EIF2B4-mutant VWM disease untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6
Localization
GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-8953854 Metabolism of RNA 2 R-HSA-1643685 Disease 1
Partners
EIF2B1EIF2B2EIF2B3EIF2B5EIF2S1EIF2S2EIF2S3
Complex memberships
eIF2B decamereIF2B regulatory subcomplex (α/β/δ)eIF2B βγδε tetramer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GSK-3 phosphorylates the largest (epsilon) subunit of eIF2B and is rapidly inactivated by insulin, linking insulin signaling to eIF2B regulation via GSK-3 inactivation. Kinase activity assay with Mono-S chromatography fractions, immunoblotting with GSK-3 isoform-specific antibodies, phosphatase-2A reversal experiment The Biochemical journal High 8397507
1998 GSK-3 phosphorylates Ser540 (Ser535 in rat) of the eIF2Bε subunit in intact cells, and this phosphorylation inhibits eIF2B activity; insulin causes dephosphorylation of this site in a PI 3-kinase-dependent manner. In vitro kinase assay, phosphorylation site identification, PI 3-kinase inhibitor studies in intact cells FEBS letters High 9468292
1997 Insulin activates eIF2B through a PI 3-kinase-dependent pathway that leads to inhibition of GSK-3; dominant negative PI 3-kinase blocks both eIF2B activation and GSK-3 inhibition, while dominant negative Sos (MAP kinase pathway) does not. Dominant negative PI 3-kinase expression, dominant negative Sos expression, rapamycin treatment, kinase activity assays FEBS letters High 9237674
1996 eIF2B is rapidly activated following T-cell mitogenic stimulation coincident with inactivation of GSK-3; phosphorylation of eIF2Bε by GSK-3 inhibits nucleotide exchange activity in vitro, providing a mechanism for rapid eIF2B activation. eIF2B activity assay, GSK-3 kinase assay, in vitro nucleotide exchange inhibition assay The Journal of biological chemistry High 8626696
1998 eIF2B is a heteropentameric GEF composed of two functionally distinct subcomplexes: a regulatory subcomplex (GCN3/α, GCD7/β, GCD2/δ) that binds eIF2(αP) with high affinity but lacks exchange activity, and a catalytic subcomplex (GCD1/γ, GCD6/ε) that has exchange activity insensitive to eIF2(αP). Binding of eIF2(αP) to the regulatory subcomplex prevents productive interaction with the catalytic subcomplex. In vitro nucleotide exchange assay, affinity binding assay, yeast regulatory mutants Genes & development High 9472020
1998 The α- and δ-subunits of eIF2B mediate sensitivity to inhibition by phosphorylated eIF2(αP): recombinant five-subunit eIF2B is inhibited by eIF2(αP), but four-subunit eIF2B lacking the α-subunit is insensitive; a point mutation in the δ-subunit also confers insensitivity. Baculovirus expression and purification of recombinant eIF2B holoprotein and subunit-deletion complexes, in vitro GEF activity assay The Journal of biological chemistry High 9582312
1996 The GCN3(α), GCD7(β), and GCD2(δ) subunits of eIF2B form a stable trimeric regulatory subcomplex (confirmed by co-immunoprecipitation); this subcomplex interacts with eIF2(αP) and mediates inhibition of eIF2B GEF activity but lacks exchange activity itself. Co-immunoprecipitation of overexpressed subunits, in vivo suppression assays, genetic analysis Molecular and cellular biology High 8887689
2001 Phosphorylated eIF2α (Ser51) tightly binds the eIF2B regulatory subcomplex (GCN3/GCD7/GCD2) in vitro in a phosphorylation-stimulated manner; this tight binding is required for inhibition of eIF2B GEF activity. Mutations in eIF2α and in GCD7 that abolish eIF2B inhibition also impair this binding. GST pulldown with recombinant phosphorylated eIF2α and eIF2B subunits, genetic suppressor analysis, in vivo competition assay Molecular and cellular biology High 11438658
2000 Phosphorylation of Ser51 of eIF2α promotes complex formation between eIF2α(P) and eIF2B and inhibits eIF2B GEF activity; the Ser51→Asp phosphomimetic mutant recapitulates these effects, while the Ser51→Ala mutant does not. Baculovirus expression of eIF2α mutants, in vitro GEF inhibition assay, eIF2–eIF2B complex formation in reticulocyte lysate Biochemistry High 11041858
2002 The catalytic domain of eIF2Bε (yeast GCD6) resides in residues 518–712; residues 518–581 are required for nucleotide exchange activity beyond eIF2 binding, and deletion of C-terminal 61 residues abolishes both functions. N-terminal half of eIF2Bε mediates complex formation with other subunits and an activation function stimulated by that complex formation. N- and C-terminal deletion analysis, in vitro GEF assay, in vivo complementation The EMBO journal High 12356745
2000 eIF2 binds specifically to the δ- and ε-subunits of eIF2B; eIF2B binds to the β-subunit of eIF2, with the binding site located in the C-terminal ~70 amino acids of eIF2β. Phosphorylation of eIF2α does not promote binding of isolated eIF2α to eIF2B but increases overall eIF2B–eIF2 affinity. Far-Western blot analysis with individual subunits The Journal of biological chemistry Medium 9446619
2001 Mammalian eIF2B acts as a GDP dissociation stimulator (releases eIF2-bound GDP even without free nucleotide); the β-subunit of eIF2B interacts with GTP; addition of eIF2Bα to preparations lacking it markedly enhances GEF activity. In vitro nucleotide release assay, GTP-binding assay, reconstitution with recombinant eIF2Bα The Journal of biological chemistry High 11323413
2005 eIF2B and eIF2 co-localize to a specific cytoplasmic body in yeast; eIF2 dynamically cycles into these foci while eIF2B remains largely resident (FRAP); three distinct strategies to reduce eIF2B GEF function all inhibit eIF2 shuttling into foci, implicating this cytoplasmic body as the site of guanine nucleotide exchange. Fluorescence microscopy co-localization, FRAP (fluorescence recovery after photobleaching), genetic and pharmacological inhibition of eIF2B The Journal of cell biology High 16157703
2013 eIF2B possesses a second activity as a GDI displacement factor (GDF): the eIF2Bγ and eIF2Bε subunits displace eIF5 (a GDI) from the eIF2•GDP/eIF5 complex prior to GEF action. GDF activity is insensitive to eIF2α phosphorylation (unlike GEF), and eIF2Bγ mutations impair GDF but not GEF function. Protein-protein interaction assays, nucleotide exchange kinetic assays, mutagenesis of eIF2Bγ Genes & development High 24352424
2014 eIF2B is a decamer (dimer of pentamers) rather than a pentamer; assembly occurs through the catalytic γ- and ε-subunits forming a tetrameric core, with regulatory subunits arranged asymmetrically; GTP binds to eIF2Bγ. Native mass spectrometry, chemical cross-linking, surface accessibility measurements, homology modelling Nature communications High 24852487
2014 Mammalian eIF2B is a decamer (dimer of eIF2B(βγδε) tetramers) stabilized by two copies of eIF2Bα; eIF2Bδ is pivotal for tetramer formation; decamers show greater eIF2 binding and activity than tetramers alone. Mass spectrometry, co-immunoprecipitation of overexpressed complexes, subunit deletion analysis FASEB journal High 24532666
2015 ISRIB is an activator of eIF2B that stabilizes eIF2B dimers; eIF2B4 (δ-subunit) contributes to the ISRIB binding site. ISRIB renders cells insensitive to eIF2α phosphorylation by enhancing eIF2B activity. Reporter-based shRNA screen, biochemical stabilization assays, ISRIB analog structure-activity relationship, cell-based translation assays eLife High 25875391
2019 Cryo-EM structures of eIF2 bound to eIF2B (dephosphorylated) reveal that the eIF2B decamer is a static platform on which one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers; phosphorylation refolds eIF2α, allowing it to contact eIF2B at a different interface and sequester it into a nonproductive complex. Cryo-electron microscopy structural determination Science High 31048491
2019 Cryo-EM and crystallographic structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2 show that the two forms bind eIF2B in completely different manners: unphosphorylated eIF2 binds in a nucleotide exchange-active mode, whereas phosphorylated eIF2 binds in an inactive mode, explaining dominant inhibition. Cryo-electron microscopy, X-ray crystallography Science High 31048492
2020 ISRIB antagonizes the ISR by allosteric antagonism: ISRIB and eIF2(αP) bind distinct sites on eIF2B; eIF2(αP) engagement of both eIF2B regulatory sites remodels the ISRIB-binding pocket, reducing ISRIB binding affinity, and vice versa. Cryo-EM shows eIF2(αP) binding converts eIF2B into a conformation unfavorable for productive eIF2 engagement. Cryo-electron microscopy, in vitro nucleotide exchange assay with mutations, cell-based ISR reporter assays Molecular cell High 33220178
2021 eIF2B assembly state regulates ISR: without the α-subunit, unassembled eIF2B tetramers accumulate and induce the ISR. ISRIB promotes tetramer-to-octamer assembly and also allosterically antagonizes the ISR within fully assembled decamers via a rocking conformational motion coupling eIF2, eIF2-P, and ISRIB binding sites. eIF2-P binding converts eIF2B decamers into 'conjoined tetramers' with reduced substrate binding and activity. In vitro assembly monitoring, cryo-EM structural analysis, ISRIB treatment of cells lacking eIF2Bα, ISR reporter assays eLife High 33688831
2018 ISRIB stabilizes VWM disease mutant eIF2B in the decameric form and restores residual catalytic GEF activity to wild-type levels; various VWM mutations (including in EIF2B4/δ-subunit) destabilize the decameric holoenzyme. Biochemical stability assays, GEF activity assays of recombinant VWM mutant eIF2B complexes, cell-based ISR activation assays eLife High 29489452
2017 NMR, fluorescence spectroscopy, and mutagenesis reveal that eIF2α phosphorylation inhibits eIF2B by destabilizing an autoregulatory intramolecular interaction within eIF2α; the first structural model for eIF2B in complex with eIF2-GDP and intermediates was proposed. NMR spectroscopy, fluorescence spectroscopy, site-directed mutagenesis, thermodynamic analysis Nucleic acids research High 29036434
2012 TLR-TRIF signaling activates eIF2B GEF activity through PP2A-mediated dephosphorylation of the eIF2Bε subunit; PP2A is itself activated by decreased Src-family-kinase-mediated tyrosine phosphorylation of its catalytic subunit, counteracting the inhibitory effect of p-eIF2α and preventing CHOP induction. eIF2B GEF activity assay, PP2A activity assay, pharmacological inhibitors, in vitro and in vivo (mouse) experiments Nature cell biology High 22231169
2015 Crystal structure of the eIF2B regulatory subcomplex (eIF2B RSC): eIF2Bβ and eIF2Bδ form a tetramer (βδ)2, and combined with a homodimer of eIF2Bα2, create a hexameric regulatory subcomplex. eIF2Bα specifically binds AMP and GMP as ligands in the ancestral catalytic site, revealing evolutionary relation to sugar isomerases. X-ray crystallography, mutational analysis, biochemical binding assays Nucleic acids research High 26384431
2007 The universally conserved residue E569 and W699 in the eIF2Bε catalytic (GEF) domain are critical for exchange activity; W699 is required for interaction with eIF2β, while E569/L568 and W699 are all required for interaction with eIF2γ, establishing that multiple contacts between eIF2γ and eIF2Bε mediate nucleotide exchange. Site-directed mutagenesis, in vitro binding assays, yeast genetic complementation Molecular and cellular biology High 17526738
2021 Sugar phosphates (e.g., glucose-6-phosphate) bind the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation, and enhance GEF activity toward eIF2. A VWM disease mutation in the eIF2Bα ligand pocket abolishes sugar phosphate binding and stimulation. Unbiased binding and activity screens, X-ray crystallography of sugar phosphate-bound eIF2B, mutagenesis of ligand pocket, VWM mutant functional analysis Nature communications High 34103529
2020 eIF2B forms enzymatically inactive filaments in starving yeast cells, triggered by starvation-induced cytosolic acidification; filament assembly (not Gcn2 kinase) is required for rapid translational downregulation and promotes stress survival and fast recovery. Live fluorescence microscopy, pH measurement, translation assays, site-specific variants, Gcn2 mutant epistasis Biology open Medium 32554487
2010 A specific isoform of eIF2Bδ (variant 1/V1) attenuates the ER stress/unfolded protein response: replacement of total eIF2Bδ with V1 renders cells insensitive to eIF2α phosphorylation (no ATF4 upregulation, no translational suppression); V1 does not interact with eIF2, unlike the canonical variant 2. Isoform-specific expression in cancer cell lines, eIF2B-eIF2 interaction assay, translation and ATF4 reporter assays The Journal of biological chemistry Medium 20709751
2011 eIF2Bα (α-subunit) is required for eIF2-mediated translational suppression in response to eIF2α phosphorylation; loss of eIF2Bα or a T41A point mutation is sufficient to overcome translational inhibition from eIF2α phosphorylation and renders normal cells susceptible to viral infection. Yeast functional complementation, mammalian cell knockdown/expression of eIF2Bα variants, virus infection susceptibility assay Journal of virology Medium 21795329
2020 Viral proteins (from a coronavirus and a picornavirus) independently acquired the ability to act as competitive inhibitors of p-eIF2–eIF2B interaction, allowing continued eIF2-GTP formation and global translation at high p-eIF2 levels that would otherwise halt translation. In vitro competition binding assay, translation assays in infected cells, viral protein expression Nature microbiology High 32690955
2021 Cryo-EM reveals that SFSV NSs viral protein binds to the α-subunit of eIF2B in a manner competitive with eIF2(αP); in the presence of NSs, eIF2B retains GEF activity even with bound eIF2(αP), allowing unimpeded translation. Cryo-electron microscopy structural analysis, in vitro nucleotide exchange assay, ribosome profiling in cells Nature communications High 34876589
2000 Drosophila eIF2Bε shows guanine nucleotide exchange activity and is phosphorylated by GSK-3 and casein kinase II; GSK-3 phosphorylation inhibits Drosophila eIF2B activity; Drosophila eIF2Bα confers regulation by phosphorylated eIF2α in yeast, and eIF2B activity in S2 cells is regulated by serum and ER stress via eIF2α phosphorylation. Cloning, in vitro GEF assay, GSK-3 and CK2 kinase assay, yeast complementation, S2 cell serum starvation and ER stress experiments The Journal of biological chemistry High 11060303
2008 RNAi inactivation of eIF2Bδ (F11A3.2) in adult C. elegans reduces global protein synthesis and extends lifespan in a DAF-16 (FOXO)-dependent manner, also conferring thermal and oxidative stress resistance. Adult-onset RNAi, 35S-methionine incorporation assay, genetic epistasis with daf-16 deletion mutant FASEB journal Medium 18728216
2001 Fusel alcohols (butanol, isoamyl alcohol) inhibit translation initiation in yeast by targeting eIF2B; a Pro180Ser variation in GCD1 (γ-subunit of eIF2B) determines sensitivity to fusel alcohol-induced translational regulation. Genetic mapping, yeast strain-specific translational inhibition assay, identification of GCD1 allelic variation The EMBO journal Medium 11707417
1998 EGF and NGF activate eIF2B in PC12 cells via PI 3-kinase; EGF activation additionally requires FRAP/mTOR signaling; GSK-3 inactivation by EGF/NGF is not rapamycin-sensitive despite eIF2B activation being rapamycin-sensitive, indicating additional regulatory inputs beyond GSK-3. PI3K inhibitor (wortmannin), rapamycin, GSK-3 and CKII kinase assays, eIF2B activity assay The Journal of biological chemistry Medium 9488678

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. The Biochemical journal 349 8397507
2001 Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nature genetics 326 11704758
2002 Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Annals of neurology 291 11835386
2001 Tight binding of the phosphorylated alpha subunit of initiation factor 2 (eIF2alpha) to the regulatory subunits of guanine nucleotide exchange factor eIF2B is required for inhibition of translation initiation. Molecular and cellular biology 283 11438658
1998 Regulation of eukaryotic initiation factor eIF2B: glycogen synthase kinase-3 phosphorylates a conserved serine which undergoes dephosphorylation in response to insulin. FEBS letters 242 9468292
1998 eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes & development 218 9472020
2015 Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. eLife 206 25875391
2019 eIF2B activator prevents neurological defects caused by a chronic integrated stress response. eLife 179 30624206
2000 Phosphorylation of serine 51 in initiation factor 2 alpha (eIF2 alpha) promotes complex formation between eIF2 alpha(P) and eIF2B and causes inhibition in the guanine nucleotide exchange activity of eIF2B. Biochemistry 152 11041858
2020 ISRIB Blunts the Integrated Stress Response by Allosterically Antagonising the Inhibitory Effect of Phosphorylated eIF2 on eIF2B. Molecular cell 150 33220178
2004 The effect of genotype on the natural history of eIF2B-related leukodystrophies. Neurology 135 15136673
1998 Implication of eIF2B rather than eIF4E in the regulation of global protein synthesis by amino acids in L6 myoblasts. The Journal of biological chemistry 132 9812990
2003 eIF2B-related disorders: antenatal onset and involvement of multiple organs. American journal of human genetics 125 14566705
1992 Phosphorylation of eukaryotic initiation factor (eIF) 2 alpha and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. The Journal of biological chemistry 116 1512215
2005 eIF2B, a mediator of general and gene-specific translational control. Biochemical Society transactions 113 16246152
1995 Modulation of tRNA(iMet), eIF-2, and eIF-2B expression shows that GCN4 translation is inversely coupled to the level of eIF-2.GTP.Met-tRNA(iMet) ternary complexes. Molecular and cellular biology 112 7565788
2019 The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility. Cancer biology & medicine 107 31119045
2012 Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B. Nature cell biology 107 22231169
2018 The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes. eLife 99 29489452
2006 The large spectrum of eIF2B-related diseases. Biochemical Society transactions 99 16246171
2019 eIF2B-catalyzed nucleotide exchange and phosphoregulation by the integrated stress response. Science (New York, N.Y.) 95 31048491
2009 Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases. Brain : a journal of neurology 92 19625339
1996 T-cell activation leads to rapid stimulation of translation initiation factor eIF2B and inactivation of glycogen synthase kinase-3. The Journal of biological chemistry 90 8626696
2019 Structural basis for eIF2B inhibition in integrated stress response. Science (New York, N.Y.) 89 31048492
2002 Characterization of the minimal catalytic domain within eIF2B: the guanine-nucleotide exchange factor for translation initiation. The EMBO journal 89 12356745
1994 The guanine nucleotide-exchange factor, eIF-2B. Biochimie 89 7893825
1997 Activation of translation initiation factor eIF2B by insulin requires phosphatidyl inositol 3-kinase. FEBS letters 86 9237674
1998 Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2alpha. Role of the alpha- and delta-subunits of eiF2b. The Journal of biological chemistry 85 9582312
2000 Identification of domains and residues within the epsilon subunit of eukaryotic translation initiation factor 2B (eIF2Bepsilon) required for guanine nucleotide exchange reveals a novel activation function promoted by eIF2B complex formation. Molecular and cellular biology 84 10805739
2018 Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. Wiley interdisciplinary reviews. RNA 79 29989343
2007 eIF2B and oligodendrocyte survival: where nature and nurture meet in bipolar disorder and schizophrenia? Schizophrenia bulletin 77 17329232
1997 Eukaryotic initiation factor 2B (eIF2B). The international journal of biochemistry & cell biology 77 9438375
2000 Endotoxin-induced decrease in muscle protein synthesis is associated with changes in eIF2B, eIF4E, and IGF-I. American journal of physiology. Endocrinology and metabolism 76 10827017
1999 Inhibition of muscle protein synthesis by alcohol is associated with modulation of eIF2B and eIF4E. The American journal of physiology 75 10444422
1996 Identification of a regulatory subcomplex in the guanine nucleotide exchange factor eIF2B that mediates inhibition by phosphorylated eIF2. Molecular and cellular biology 75 8887689
1996 Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. The Journal of biological chemistry 73 8567668
2003 Reduced amino acid availability inhibits muscle protein synthesis and decreases activity of initiation factor eIF2B. American journal of physiology. Endocrinology and metabolism 72 12556349
2005 Heightened stress response in primary fibroblasts expressing mutant eIF2B genes from CACH/VWM leukodystrophy patients. Human genetics 65 16041584
2001 A novel eIF2B-dependent mechanism of translational control in yeast as a response to fusel alcohols. The EMBO journal 65 11707417
2000 Impaired protein synthesis induced by acute alcohol intoxication is associated with changes in eIF4E in muscle and eIF2B in liver. Alcoholism, clinical and experimental research 65 10776669
2013 eIF2B promotes eIF5 dissociation from eIF2*GDP to facilitate guanine nucleotide exchange for translation initiation. Genes & development 64 24352424
2017 Novel mechanisms of eIF2B action and regulation by eIF2α phosphorylation. Nucleic acids research 59 29036434
2014 eIF2B is a decameric guanine nucleotide exchange factor with a γ2ε2 tetrameric core. Nature communications 59 24852487
2011 Severity of vanishing white matter disease does not correlate with deficits in eIF2B activity or the integrity of eIF2B complexes. Human mutation 59 21560189
2005 PKR and GCN2 kinases and guanine nucleotide exchange factor eukaryotic translation initiation factor 2B (eIF2B) recognize overlapping surfaces on eIF2alpha. Molecular and cellular biology 58 15798194
2021 eIF2B conformation and assembly state regulate the integrated stress response. eLife 57 33688831
1994 Purification and characterization of eukaryotic translational initiation factor eIF-2B from liver. Biochimica et biophysica acta 56 7803480
2014 Analysis of the subunit organization of the eIF2B complex reveals new insights into its structure and regulation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 53 24532666
1998 Nerve and epidermal growth factor induce protein synthesis and eIF2B activation in PC12 cells. The Journal of biological chemistry 53 9488678
2015 eIF2B: recent structural and functional insights into a key regulator of translation. Biochemical Society transactions 52 26614666
1994 Mutations in the GCD7 subunit of yeast guanine nucleotide exchange factor eIF-2B overcome the inhibitory effects of phosphorylated eIF-2 on translation initiation. Molecular and cellular biology 52 8164676
2005 Dynamic cycling of eIF2 through a large eIF2B-containing cytoplasmic body: implications for translation control. The Journal of cell biology 51 16157703
1997 Inactivation of eIF2B and phosphorylation of PHAS-I in heat-shocked rat hepatoma cells. The Journal of biological chemistry 48 9341116
1994 Use of monoclonal antibodies to study the structure and function of eukaryotic protein synthesis initiation factor eIF-2B. European journal of biochemistry 48 8168527
1998 Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B. The Journal of biological chemistry 44 9446619
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