Affinage

EIF2B2

Translation initiation factor eIF2B subunit beta · UniProt P49770

Length
351 aa
Mass
39.0 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2B2 encodes the β-subunit of eIF2B, a heterodecameric guanine nucleotide exchange factor (GEF) and GDI displacement factor (GDF) for eIF2 that is essential for translation initiation. Within the decamer (two copies each of α–ε subunits), the β-subunit is part of the regulatory subcomplex (α/β/δ) that binds phosphorylated eIF2α with high affinity to competitively inhibit nucleotide exchange, thereby transducing the integrated stress response, while the catalytic γ/ε subcomplex catalyzes GDP→GTP exchange on eIF2 through direct contacts with eIF2β and eIF2γ (PMID:8887689, PMID:31048491, PMID:31048492). eIF2B activity is modulated by GSK-3–mediated phosphorylation of eIF2Bε (Ser535/540), reversed by insulin/PI3K signaling and PP2A, and by allosteric stabilization of the decamer through the small molecule ISRIB or metabolic ligands such as sugar phosphates (PMID:9468292, PMID:25875391, PMID:34103529). Mutations in EIF2B2 cause Vanishing White Matter disease (leukoencephalopathy with vanishing white matter) by destabilizing the decameric assembly and hypersuppressing translation during stress, disrupting GADD34-mediated feedback recovery of phospho-eIF2α (PMID:29632131, PMID:29489452).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1993 High

    Establishing that eIF2B is regulated by insulin-responsive phosphorylation resolved how growth-factor signaling controls translation initiation: GSK-3 directly phosphorylates the eIF2Bε subunit to inhibit GEF activity, and insulin reverses this via GSK-3 inactivation.

    Evidence Kinase assays on Mono-S fractions, GSK-3 isoform-specific immunoblots, PP2A reversal in CHO cells expressing human insulin receptor

    PMID:8397507

    Open questions at the time
    • Exact phosphorylation site on eIF2Bε not yet mapped
    • Pathway between insulin receptor and GSK-3 undefined
  2. 1997 High

    Defining PI3K as the intermediate between insulin signaling and GSK-3/eIF2B placed eIF2B activation within the canonical PI3K-Akt pathway, establishing eIF2B as a downstream translational effector of growth factor signaling.

    Evidence Dominant-negative PI3K, wortmannin, rapamycin insensitivity; GSK-3 and eIF2B activity assays

    PMID:9237674

    Open questions at the time
    • Whether Akt directly phosphorylates GSK-3 to control eIF2B not formally shown here
    • Tissue-specific regulation not addressed
  3. 1998 High

    Identifying the eIF2B regulatory (α/β/δ) and catalytic (γ/ε) subcomplexes, and showing that the regulatory subcomplex mediates phospho-eIF2α sensitivity while lacking exchange activity, defined the bipartite architecture of eIF2B and the mechanistic basis for ISR transduction.

    Evidence Purified yeast and mammalian subcomplexes; in vitro GEF assays with phospho- and unphospho-eIF2; baculovirus reconstitution; mutagenesis of α and δ subunits

    PMID:8887689 PMID:9472020 PMID:9582312

    Open questions at the time
    • Stoichiometry of the holoenzyme unknown
    • How phospho-eIF2α binding to regulatory subcomplex inhibits catalytic subcomplex activity unclear
  4. 1998 High

    Mapping the GSK-3 phosphorylation site to Ser540 (Ser535) on eIF2Bε and demonstrating that this single phosphorylation inhibits GEF activity provided the molecular target for PI3K-dependent translational control.

    Evidence Site-directed mutagenesis, in vitro kinase assay, phosphorylation-state analysis in intact cells with PI3K inhibitors

    PMID:9468292

    Open questions at the time
    • Whether additional sites contribute to regulation not excluded
    • Structural basis of inhibition by Ser540 phosphorylation unknown
  5. 2000 High

    Demonstrating that a C-terminal fragment of eIF2Bε (residues 518–712) is the minimal catalytic domain sufficient for nucleotide exchange separated catalytic and regulatory functions within a single subunit and showed that complex formation with other subunits enhances activity.

    Evidence Deletion analysis of yeast GCD6 in vitro and in vivo; complementation assays; GEF activity assays

    PMID:10805739 PMID:12356745

    Open questions at the time
    • How N-terminal activation domain of eIF2Bε communicates with catalytic domain structurally undefined
    • Minimal domain lacks ISR regulation
  6. 2001 High

    Showing that phospho-eIF2α binds tightly and specifically to the regulatory subcomplex while mutations abolishing this binding also abolish GEF inhibition established competitive substrate sequestration as the inhibition mechanism.

    Evidence GST pulldown with phospho- and unphospho-eIF2α; genetic suppressor analysis in yeast

    PMID:11041858 PMID:11438658

    Open questions at the time
    • Structural details of the phospho-eIF2α–regulatory subcomplex interface unknown
    • Whether sequestration is the sole mechanism or allosteric effects contribute unclear
  7. 2005 High

    Discovering that eIF2B and eIF2 co-localize to a specific cytoplasmic body in yeast where eIF2 dynamically shuttles for nucleotide exchange revealed that GEF activity is spatially organized.

    Evidence Fluorescence microscopy co-localization, FRAP, genetic and pharmacological perturbation of eIF2B activity in yeast

    PMID:16157703

    Open questions at the time
    • Whether mammalian eIF2B forms equivalent bodies not shown
    • Molecular determinants of body formation unknown
  8. 2007 High

    Alanine-scanning mutagenesis of eIF2Bε showed that the catalytic domain contacts both eIF2β and eIF2γ through spatially separated surfaces (~40 Å apart), establishing that nucleotide exchange requires multipoint engagement of the substrate.

    Evidence Conserved-residue mutagenesis, yeast complementation, in vitro GEF and binding assays

    PMID:17526738

    Open questions at the time
    • Atomic structure of the eIF2B–eIF2 interface not yet available
    • Whether the two contact surfaces function sequentially or simultaneously unknown
  9. 2012 High

    Demonstrating that TLR-TRIF signaling activates eIF2B through PP2A-mediated dephosphorylation of eIF2Bε revealed an immune-cell-specific input to translational control during ER stress.

    Evidence PP2A activity assay, phospho-state analysis of eIF2Bε, siRNA knockdown, in vivo mouse ER stress model with TLR activation

    PMID:22231169

    Open questions at the time
    • Which Src-family kinase member mediates PP2A phosphorylation in this context not identified
    • Generalizability beyond macrophage/innate immunity not tested
  10. 2013 High

    Identifying eIF2B's GDI displacement factor (GDF) activity — mechanistically separable from GEF activity — showed that eIF2Bγ/ε first displace eIF5 (the GDI) from eIF2·GDP before catalyzing exchange, and that ISR phospho-eIF2α selectively inhibits GEF but not GDF.

    Evidence Protein interaction and kinetic assays distinguishing GDF from GEF; eIF2Bγ mutations selectively impairing GDF

    PMID:24352424

    Open questions at the time
    • Structural basis of GDF activity unknown
    • Whether GDF is rate-limiting in vivo not established
  11. 2014 High

    Native mass spectrometry established that eIF2B is a heterodecamer (dimer of pentamers) rather than a pentamer, with eIF2Bα stabilizing the dimer and eIF2Bδ pivotal for tetramer formation, explaining why the holoenzyme has greater substrate-binding and catalytic activity than subcomplexes.

    Evidence Native MS, chemical cross-linking, co-IP, eIF2-binding assays, tissue-level subunit stoichiometry

    PMID:24532666 PMID:24852487

    Open questions at the time
    • High-resolution structure not yet available
    • How dimerization enhances catalysis mechanistically unclear
  12. 2015 High

    The discovery that ISRIB activates eIF2B by stabilizing its decameric assembly and rendering cells insensitive to eIF2α phosphorylation provided both a pharmacological tool and a therapeutic lead for ISR-related diseases.

    Evidence shRNA screen identifying eIF2B as ISRIB target; biochemical stabilization of eIF2B dimers; eIF2B4 (δ) as binding site component; cell-based ISR assay

    PMID:25875391

    Open questions at the time
    • Atomic details of ISRIB binding site on eIF2B not resolved
    • In vivo pharmacokinetics and CNS penetrance not addressed
  13. 2015 High

    Crystal structures of the eIF2B regulatory subcomplex revealed the hexameric (α₂β₂δ₂) architecture and showed that eIF2Bα binds nucleotide ligands (AMP/GMP) in an ancestral sugar-phosphatase pocket, linking metabolic sensing to translational control.

    Evidence X-ray crystallography of eIF2Bβ, δ, and (βδ)₂ from Chaetomium thermophilum; ligand binding assays; mutational analysis

    PMID:26384431

    Open questions at the time
    • Physiological significance of nucleotide binding to eIF2Bα unclear
    • Whether AMP/GMP binding modulates ISR sensitivity untested
  14. 2016 High

    The first crystal structure of a full eIF2B decamer (S. pombe) provided the structural framework for understanding how phospho-eIF2α Ser51 inhibits GEF activity at the holoenzyme level.

    Evidence X-ray crystallography of full decamer; structure-based in vitro GEF analyses

    PMID:27627185

    Open questions at the time
    • Structure of eIF2B bound to eIF2 substrate not available
    • Mammalian eIF2B structure not yet determined
  15. 2017 High

    Demonstrating that EIF2B2 mutations in VWM patient cells cause hypersuppression of translation during ER stress — by disrupting GADD34-mediated feedback dephosphorylation of phospho-eIF2α — defined the pathogenic mechanism of Vanishing White Matter disease at the translational level.

    Evidence Translation rate measurements in patient fibroblasts; ISR reporters; GADD34 feedback analysis; pharmacological rescue with ISRIB and PERK inhibitor

    PMID:29632131

    Open questions at the time
    • Why white matter is selectively vulnerable not explained
    • Whether all VWM-causing EIF2B2 alleles act through the same mechanism not tested
  16. 2018 High

    Showing that VWM disease mutations destabilize the eIF2B decamer and that ISRIB rescues both stability and catalytic activity connected the biophysical defect (decamer instability) to pathology and validated a therapeutic strategy.

    Evidence Biochemical stability assays, GEF activity assays, SEC/MS of mutant complexes, cell-based ISR rescue in VWMD patient cells

    PMID:29489452

    Open questions at the time
    • In vivo efficacy of ISRIB in VWM animal models not shown
    • Not all VWM mutations tested
  17. 2019 High

    Cryo-EM structures of eIF2B bound to unphosphorylated and phosphorylated eIF2 revealed two completely distinct binding modes — productive (exchange-competent) versus nonproductive (inhibitory) — providing the atomic-level mechanism for ISR-mediated translational control.

    Evidence Cryo-EM and X-ray crystallography of eIF2B·eIF2 complexes in both phosphorylation states, from two independent groups

    PMID:31048491 PMID:31048492

    Open questions at the time
    • Transition dynamics between productive and nonproductive modes not captured
    • Role of individual regulatory subunits including β in the conformational switch not fully dissected
  18. 2020 High

    Structural and biochemical demonstration that ISRIB and phospho-eIF2α reciprocally oppose each other's binding to eIF2B through allosteric remodeling of shared pockets established ISRIB's mechanism as direct antagonism of the ISR conformational switch.

    Evidence Cryo-EM of eIF2B with eIF2(αP) and ISRIB; in vitro nucleotide exchange assay; ISRIB-resistant mutants

    PMID:33220178

    Open questions at the time
    • Whether ISRIB efficacy varies across eIF2B mutant backgrounds (e.g., different VWM alleles) not systematically explored
  19. 2020 Medium

    Discovery that viral proteins from diverse virus families independently evolved to competitively block phospho-eIF2 binding to eIF2B demonstrated that the regulatory subcomplex interface is a convergent target for immune evasion.

    Evidence Cell-based ISR reporter assays; competition binding experiments; translation assays in virus-infected cells

    PMID:32690955

    Open questions at the time
    • Direct structural visualization of viral protein–eIF2B interaction not shown in this study
    • Breadth across additional virus families not tested
  20. 2021 High

    Demonstrating that eIF2(αP) converts active eIF2B decamers into 'conjoined tetramers' with diminished catalysis via a rocking motion, and that ISRIB rescues assembly even without eIF2Bα, unified the assembly-state and allosteric models of ISR regulation.

    Evidence Cryo-EM; in vitro assembly monitoring; ISRIB treatment; eIF2Bα knockout cells

    PMID:33688831

    Open questions at the time
    • Whether conjoined tetramers form in vivo under physiological stress not directly demonstrated
    • Contribution of eIF2Bβ to the rocking conformational change not isolated
  21. 2021 High

    Identification of sugar phosphates (e.g., glucose-6-phosphate) as natural ligands that occupy an ancestral catalytic site in eIF2Bα, promote decamer formation, and enhance GEF activity linked cellular metabolic state to eIF2B regulation independently of phospho-eIF2α.

    Evidence Unbiased ligand-binding screens; enzymatic activity assays; structural studies; VWM mutant analysis

    PMID:34103529

    Open questions at the time
    • Physiological range of sugar-phosphate concentrations needed to modulate eIF2B in vivo not established
    • Whether eIF2Bβ pocket also binds metabolites not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The specific contribution of the eIF2Bβ subunit to decamer assembly, ISR sensing, and GEF catalysis — as opposed to the roles of the structurally related α and δ subunits — remains incompletely resolved at the atomic level.
  • No subunit-specific deletion or point-mutation series for EIF2B2 dissecting its unique versus redundant roles within the regulatory subcomplex
  • Genotype–phenotype map for EIF2B2 VWM alleles incomplete
  • Whether eIF2Bβ has ligand-binding or metabolic-sensing capacity analogous to eIF2Bα is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7
Localization
GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 2 R-HSA-8953854 Metabolism of RNA 1
Partners
EIF2B1EIF2B3EIF2B4EIF2B5EIF2S1EIF2S2EIF2S3EIF5
Complex memberships
eIF2B decamer (α₂β₂γ₂δ₂ε₂)eIF2B regulatory subcomplex (α₂β₂δ₂)

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 GSK-3 phosphorylates the epsilon subunit of eIF2B, and insulin rapidly inactivates GSK-3 (via phosphorylation of GSK-3), leading to reduced phosphorylation and activation of eIF2B; the effect is reversed by protein phosphatase-2A. Kinase assays on Mono-S fractions, immunoblotting with GSK-3α/β isoform-specific antibodies, phosphatase treatment, CHO cells expressing human insulin receptor The Biochemical journal High 8397507
1998 GSK-3 phosphorylates Ser540 (Ser535 in some numbering) of the eIF2Bε subunit, and this phosphorylation inhibits eIF2B nucleotide exchange activity; insulin causes dephosphorylation of this site in a PI3K-dependent manner. Site-directed mutagenesis to identify phosphorylation site, in vitro kinase assay showing GSK-3 inhibits eIF2B activity, phosphorylation state measured in intact cells with PI3K inhibitors FEBS letters High 9468292
1996 The GCN3 (α), GCD7 (β), and GCD2 (δ) subunits of yeast eIF2B form a stable regulatory subcomplex that mediates inhibition of eIF2B by phosphorylated eIF2α; this subcomplex lacks nucleotide exchange activity. Coimmunoprecipitation of overexpressed subunits, in vivo genetic suppressor analysis, eIF2B activity assays in subunit deletion strains Molecular and cellular biology High 8887689
1998 Yeast eIF2B comprises two functional subcomplexes: a regulatory subcomplex (GCN3/GCD7/GCD2) that binds eIF2 with higher affinity for phosphorylated eIF2 but lacks exchange activity, and a catalytic subcomplex (GCD1/GCD6) that catalyzes GDP-GTP exchange and is not inhibited by phospho-eIF2. In vitro nucleotide-exchange assay with purified yeast eIF2B and eIF2; affinity-binding assay; characterization of regulatory mutations in GCN3 and GCD7 Genes & development High 9472020
2001 Phosphorylated eIF2α (Ser51-P) binds tightly to the eIF2B regulatory subcomplex (containing GCD7/β and GCD2/δ subunits) in vitro, and this tight binding is required for inhibition of eIF2B guanine nucleotide exchange activity; mutations in eIF2α Ser51 or in GCD7 that block inhibition also abolish this interaction. GST pulldown of recombinant eIF2α (phosphorylated and unphosphorylated) with eIF2B regulatory subcomplex; genetic suppressor analysis; in vitro stimulation of binding by Ser51 phosphorylation Molecular and cellular biology High 11438658
2000 Phosphorylation of eIF2α Ser51 promotes complex formation between phospho-eIF2α and eIF2B, inhibiting eIF2B guanine nucleotide exchange activity; the Ser51Asp (phosphomimetic) mutant but not Ser51Ala mimics this inhibition. Baculovirus expression of wild-type, S51A, and S51D eIF2α mutants; in vitro GNE assay in reticulocyte lysate; interaction measured by co-precipitation Biochemistry High 11041858
1998 The α- and δ-subunits of mammalian eIF2B mediate sensitivity to inhibition by phosphorylated eIF2; eIF2B lacking the α-subunit is insensitive to eIF2(αP) and can exchange guanine nucleotides using eIF2(αP) as substrate; a double point mutation in the δ-subunit also confers insensitivity. Baculovirus co-expression of all five rat eIF2B subunits; purification of holoprotein and four-subunit complex; in vitro GNE assay with phosphorylated and unphosphorylated eIF2 The Journal of biological chemistry High 9582312
1998 eIF2 interacts with eIF2B specifically through the δ- and ε-subunits of eIF2B, and the binding site on eIF2β for eIF2B subunits maps to approximately 70 amino acids at the C-terminus; phosphorylation of eIF2α does not promote binding of eIF2B to isolated eIF2α but increases overall affinity of eIF2B for the eIF2 heterotrimer. Far-Western blot analysis mapping eIF2-eIF2B inter-subunit contacts; binding experiments with phosphorylated eIF2 The Journal of biological chemistry Medium 9446619
2000 The C-terminal region of the yeast eIF2Bε subunit (residues 518–712) constitutes the catalytic domain sufficient for nucleotide exchange activity and eIF2 binding; the N-terminal half of eIF2Bε is an activation domain that responds to complex formation with other eIF2B subunits to enhance exchange rate. N-terminal and C-terminal deletion analysis of yeast GCD6 (eIF2Bε) in vitro and in vivo; yeast complementation assays; GEF activity assays Molecular and cellular biology High 10805739
2002 The smallest catalytically active fragment of eIF2Bε (yeast Gcd6p residues 518–712) is sufficient for nucleotide exchange; deletion to residue 581 retains eIF2 binding but abolishes exchange, separating binding from catalytic function. In vitro GEF activity assays with N-terminal deletion series; eIF2-binding assays; in vivo complementation The EMBO journal High 12356745
2001 Mammalian eIF2B acts as a GDP dissociation stimulator (GDS) protein, releasing eIF2-bound GDP even without free nucleotide; the β-subunit of eIF2B, not the ε-subunit, interacts with GTP; the α-subunit is required for full exchange activity of the mammalian holoenzyme. In vitro GDP dissociation assay with purified mammalian eIF2B; GTP-binding assay of individual subunits; reconstitution of activity by adding recombinant eIF2Bα to α-deficient preparations The Journal of biological chemistry High 11323413
2005 eIF2B and eIF2 co-localize to a specific large cytoplasmic body in yeast; eIF2 dynamically shuttles into these foci (FRAP analysis), while eIF2B is largely resident; three independent strategies to reduce eIF2B GEF activity all inhibit eIF2 shuttling, implicating this body as the site of guanine nucleotide exchange. Fluorescence microscopy co-localization; FRAP; genetic and pharmacological inhibition of eIF2B activity combined with localization readout The Journal of cell biology High 16157703
2007 The eIF2B conserved residue E569 in the eIF2Bε catalytic domain is universally essential for GEF activity; W699 on a separate surface (~40 Å away) is critical for interaction with eIF2β; residues L568/E569 and W699 both contact eIF2γ, establishing that multiple surfaces of eIF2Bε mediate nucleotide exchange through contacts with both eIF2β and eIF2γ. Alanine-scanning mutagenesis of conserved surface residues; yeast complementation; in vitro GEF activity assay; binding assays with eIF2 subunits Molecular and cellular biology High 17526738
2014 eIF2B is a decamer (dimer of pentamers) rather than a pentamer, assembled through catalytic γ- and ε-subunits as a core with regulatory subunits arranged in asymmetric trimers; GTP binds to eIF2Bγ; cross-linking places eIF2 contacts at interfaces relevant to nucleotide exchange and its control. Native mass spectrometry, chemical cross-linking, surface accessibility measurements, homology modelling Nature communications High 24852487
2014 Mammalian eIF2B is a decamer (dimer of eIF2BβγδεΑ pentamers), stabilized by two copies of eIF2Bα; eIF2Bδ plays a pivotal role in formation of the eIF2B(βγδε) tetramer; decameric eIF2B shows greater eIF2-binding activity than tetramers, explaining higher activity of the holoenzyme. Native mass spectrometry, co-immunoprecipitation of overexpressed complexes, eIF2-binding assays, analysis of eIF2B subunit levels across mouse tissues FASEB journal High 24532666
2013 eIF2B has a GDI displacement factor (GDF) activity: the eIF2Bγ and eIF2Bε subunits displace eIF5 (which acts as a GDI for eIF2·GDP) from the eIF2·GDP/eIF5 complex prior to GEF action; GDF activity is insensitive to eIF2α phosphorylation (unlike GEF), and eIF2Bγ mutations impairing GCN4 control selectively impair GDF but not GEF function. Protein-protein interaction assays; nucleotide exchange kinetics; genetic analysis of eIF2Bγ mutations; separation of GDF and GEF activities Genes & development High 24352424
2015 ISRIB (a small molecule) activates eIF2B by stabilizing eIF2B dimers (decamers); ISRIB activity requires eIF2B (shown by shRNA screen); the eIF2B4 (δ-subunit) contributes to the ISRIB binding site; ISRIB renders cells insensitive to eIF2α phosphorylation by activating eIF2B. Reporter-based shRNA screen; biochemical stabilization of eIF2B dimers; structural analysis; cell-based ISR assay; development of analog series eLife High 25875391
2018 VWM disease mutations in eIF2B destabilize the decameric eIF2B holoenzyme; ISRIB rescues stability of VWMD mutant eIF2B by stabilizing the decameric form and restores residual catalytic activity to wild-type levels; ISRIB blocks ISR activation in VWMD patient cells. Biochemical stability assays of mutant eIF2B complexes; GEF activity assays; cell-based ISR reporter assays; SEC/MS analysis of complex assembly eLife High 29489452
2019 Cryo-EM structures of eIF2 bound to eIF2B reveal that the eIF2B heterodecamer is a static platform; one or two flexible eIF2 trimers bind and align with eIF2B's bipartite catalytic centers to catalyze nucleotide exchange; phosphorylation refolds eIF2α to contact eIF2B at a different interface, sequestering it in a nonproductive complex. Cryo-electron microscopy structural determination Science High 31048491
2019 Cryo-EM and crystal structures of eIF2B in complex with unphosphorylated or phosphorylated eIF2 show that the two forms bind eIF2B in completely different modes: unphosphorylated eIF2 in a nucleotide exchange-active mode, phosphorylated eIF2 in an exchange-inactive mode that dominantly inhibits eIF2B. Cryo-electron microscopy and X-ray crystallography of eIF2B·eIF2 complexes Science High 31048492
2020 ISRIB antagonizes the ISR by allosteric mechanism: ISRIB-mediated acceleration of eIF2B nucleotide exchange is observed preferentially in the presence of phospho-eIF2; eIF2(αP) engagement of both eIF2B regulatory sites remodels the ISRIB-binding pocket and exchange-active pockets; eIF2(αP) and ISRIB reciprocally oppose each other's binding to eIF2B. Cryo-EM of eIF2B with eIF2(αP) and ISRIB; in vitro nucleotide exchange assay; eIF2B binding studies with ISR inhibitor and inhibitor-resistant mutants Molecular cell High 33220178
2021 eIF2B assembly state regulates ISR: in the absence of eIF2Bα, unassembled eIF2B tetramer subcomplexes accumulate and induce ISR; ISRIB drives assembly of inactive tetramers into active octamers/decamers; cryo-EM reveals eIF2(αP) converts eIF2B decamers into 'conjoined tetramers' with diminished substrate binding and catalytic activity via a conformational rocking motion. Cryo-EM; in vitro assembly/disassembly monitoring; in vivo ISRIB treatment; eIF2Bα knockout cell lines eLife High 33688831
2012 TLR-TRIF signaling activates eIF2B GEF activity through PP2A-mediated serine dephosphorylation of the eIF2Bε subunit; PP2A is itself activated by decreased Src-family-kinase-induced tyrosine phosphorylation of its catalytic subunit; this pathway suppresses CHOP induction and translational repression in ER-stressed cells. PP2A activity assay; phosphorylation state analysis of eIF2Bε; siRNA knockdown of pathway components; in vivo mouse model of ER stress with TLR activation Nature cell biology High 22231169
2017 EIF2B2 mutations in VWMD patient cells hypersuppress translation during the ISR (ER stress), delaying stress-induced gene expression and interrupting GADD34-mediated negative feedback dephosphorylation of phospho-eIF2α, causing prolonged translational hyperrepression and failure to recover from stress. Translation rate measurements in patient fibroblasts; ISR reporter assays; GADD34 feedback analysis; small-molecule rescue (ISRIB and PERK inhibitor) in patient cells RNA High 29632131
2021 Sugar phosphates (e.g., glucose-6-phosphate) occupy an ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation, and enhance eIF2B GEF activity; a VWM disease mutation in the eIF2Bα ligand-binding pocket fails to engage sugar phosphates and is not stimulated by them. Unbiased ligand binding screens; enzymatic activity assays; structural studies of eIF2Bα with sugar phosphate ligands; analysis of VWM mutant Nature communications High 34103529
2021 SFSV nonstructural protein NSs binds to the α-subunit of eIF2B in a manner competitive with phospho-eIF2α, allowing eIF2B to retain nucleotide exchange activity even in the presence of phospho-eIF2; cryo-EM of eIF2B·NSs·unphosphorylated eIF2 complex reveals the structural basis for ISR suppression. Cryo-EM structural determination; in vitro GEF activity assay in presence of NSs and eIF2(αP); ribosome profiling in NSs-expressing cells Nature communications High 34876589
2020 Viral proteins (from a coronavirus and a picornavirus) independently acquired the ability to act as competitive inhibitors of phospho-eIF2–eIF2B interaction, allowing continued eIF2B-mediated GTP exchange and global translation despite high phospho-eIF2 levels. Cell-based ISR reporter assays; competition binding experiments; translation assays in virus-infected cells Nature microbiology Medium 32690955
1997 Insulin activates eIF2B through a signaling pathway requiring PI3K; activation is blocked by dominant-negative PI3K and PI3K inhibitors but not rapamycin or a Sos mutant; eIF2B and GSK-3 are regulated reciprocally, and dominant-negative PI3K abolishes insulin-induced GSK-3 inhibition, placing PI3K upstream of GSK-3 in the eIF2B activation pathway. PI3K inhibitors (wortmannin), dominant-negative PI3K/Sos mutants, GSK-3 and eIF2B activity assays, rapamycin treatment FEBS letters High 9237674
2001 In S. cerevisiae, a proline-to-serine allelic variant at position 180 of the GCD1 (eIF2Bγ) subunit confers translational regulation in response to fusel alcohols; fusel alcohols target eIF2B to inhibit translation initiation. Genetic mapping; strain-specific phenotypic analysis; translation assays in eIF2B subunit mutants The EMBO journal Medium 11707417
2020 Under starvation-induced cytosolic acidification, yeast eIF2B forms enzymatically inactive filaments that promote rapid and efficient downregulation of translation; filamentation is independent of the Gcn2 kinase pathway and site-specific variants suggest assembly leads to inactive filaments supporting stress survival and fast recovery. Fluorescence microscopy of eIF2B filaments; pH measurements; site-directed mutagenesis; translation assays in filament-incompetent mutants; stress survival assays Biology open Medium 32554487
2015 Crystal structure of the eIF2B regulatory subcomplex (RSC) reveals it exists as a hexamer composed of two eIF2Bβδ heterodimers and one eIF2Bα2 homodimer; eIF2Bα specifically binds AMP and GMP as ligands in a pocket homologous to sugar-metabolizing enzymes; structural and mutational data define how RSC interacts with eIF2 and mediates inhibition. X-ray crystallography of eIF2Bβ, eIF2Bδ, and eIF2B(βδ)2 from Chaetomium thermophilum; solution biochemistry showing hexameric assembly; mutational analysis; ligand binding assays Nucleic acids research High 26384431
2016 Crystal structure of Schizosaccharomyces pombe eIF2B decamer reveals the structural mechanism by which phosphorylation of eIF2α Ser51 inhibits eIF2B GEF activity; structure-based in vitro analyses confirm mechanism. X-ray crystallography of full eIF2B decamer; structure-based in vitro GEF activity analyses The FEBS journal High 27627185
2017 eIF2α phosphorylation destabilizes an autoregulatory intramolecular interaction within eIF2α (novel inhibition mechanism); NMR and fluorescence spectroscopy provide the first structural model of the eIF2B·eIF2-GDP complex and intermediates including apo-eIF2 and eIF2-GTP, directly informing the catalytic mechanism. NMR spectroscopy; fluorescence spectroscopy; site-directed mutagenesis; thermodynamic analysis Nucleic acids research High 29036434
2019 RGS2, via its eIF2B-interacting domain, interacts with eIF2B and inhibits global protein synthesis; this interaction selectively promotes translational upregulation of ATF4 and CHOP in a manner independent of eIF2α phosphorylation. Expression of full-length RGS2 and its eIF2B-binding domain fragment; translation rate assays; ATF4/CHOP protein level measurements; cell-based ISR assays Cellular signalling Medium 30826455

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
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