Affinage

EIF4G1

Eukaryotic translation initiation factor 4 gamma 1 · UniProt Q04637

Round 2 corrected
Length
1599 aa
Mass
175.5 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF4G1 is a modular scaffold protein that nucleates the eIF4F translation initiation complex, coordinating cap-dependent and IRES-dependent mRNA recruitment to the ribosome by simultaneously engaging eIF4E (via a shared motif competed by 4E-BPs), eIF4A (via bipartite HEAT-repeat contacts that induce a half-open helicase conformation accelerating ATP hydrolysis), eIF3 (through subunits c/d/e), PABP (circularizing mRNA), and Mnk1 kinase (enabling eIF4E Ser209 phosphorylation) (PMID:8521827, PMID:21062831, PMID:24092755, PMID:9003792, PMID:9878069). Its scaffolding activity is tuned by phosphorylation — mTOR-dependent stimulation of eIF4G–eIF3 association promotes translation, Pak2 phosphorylation at S896 inhibits cap binding under stress, and Cdk1:cyclin B phosphorylation at Ser1232 during mitosis reduces eIF4A–RNA association — and by proteolytic remodeling through picornaviral 2A protease, caspases, and the 20S proteasome (PMID:16541103, PMID:16281055, PMID:24248602, PMID:3039165, PMID:9821956, PMID:15546617). eIF4G1 also forms a mutually exclusive complex with eIF1 that promotes ribosomal scanning, distinct from the eIF4E-bound complex that drives cap-proximal TISU-element translation, and a neuron-specific microexon acts as a translational brake whose loss causes ribosome stalling, synaptic protein upregulation, stress granule coalescence, and cognitive deficits in mice (PMID:29987188, PMID:31999954). Missense mutations in EIF4G1 (p.Ala502Val disrupting eIF4E binding; p.Arg1205His disrupting eIF3e binding) segregate with familial Parkinson's disease and increase oxidative stress vulnerability (PMID:21907011).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1987 High

    Identifying the mechanism by which picornaviruses shut off host translation, this study established that poliovirus 2A protease is responsible for eIF4G (p220) cleavage, providing the first evidence that eIF4G is a rate-limiting target of translational control.

    Evidence In vitro translation of 2A-encoding RNA with antibody inhibition and mutagenesis

    PMID:3039165

    Open questions at the time
    • Precise cleavage site not mapped in this study
    • Consequences for IRES-driven translation not yet tested
  2. 1995 High

    The question of how cap-dependent translation is regulated was answered by demonstrating that 4E-BP1 competes with eIF4G for eIF4E binding through a shared 12-amino-acid motif, establishing the 4E-BP/eIF4G competition as a central regulatory node.

    Evidence Competitive binding assays, mutagenesis of eIF4G and 4E-BP1, in vitro translation and 48S complex formation

    PMID:7651417 PMID:8521827

    Open questions at the time
    • Structural basis of the shared motif not yet resolved
    • In vivo stoichiometry of competition not determined
  3. 1996 High

    The molecular basis of mRNA circularization was revealed by showing that yeast eIF4G directly binds PABP through a defined N-terminal domain, creating a cap–poly(A) bridge that enhances translation of polyadenylated mRNAs.

    Evidence Co-purification, co-IP, and recombinant binding assays with deletion mapping in yeast

    PMID:10996799 PMID:9003792

    Open questions at the time
    • Structural details of the mammalian eIF4G–PABP interface not determined
    • Relative contribution to translation efficiency versus mRNA stability unclear
  4. 1999 High

    The mechanism of eIF4E phosphorylation was resolved: eIF4G recruits Mnk1 kinase to the eIF4F complex via its C-terminal region, positioning Mnk1 to phosphorylate eIF4E at Ser209, and this docking platform is hijacked by adenovirus 100k protein to displace Mnk1 and suppress host translation.

    Evidence Co-IP, in vitro kinase assays, eIF4E binding-deficient mutants, adenovirus temperature-sensitive mutant experiments

    PMID:10880459 PMID:9878069

    Open questions at the time
    • Whether Mnk2 uses an identical docking site not resolved
    • Physiological consequence of eIF4E Ser209 phosphorylation still debated
  5. 2001 High

    The structural architecture of eIF4G's central domain was established: X-ray crystallography revealed a crescent-shaped HEAT-repeat fold with adjacent surfaces for eIF4A and IRES binding, and functional mutagenesis of these surfaces confirmed their requirement for 48S complex formation.

    Evidence X-ray crystallography at 2.4 Å of eIF4GII middle domain, structure-based mutagenesis, 48S reconstitution

    PMID:10913184 PMID:11172724

    Open questions at the time
    • Full-length eIF4G structure not determined
    • Conformational dynamics of the HEAT domain upon partner binding unknown
  6. 2003 High

    Beyond cap binding, eIF4G was shown to directly contact mRNA through three distinct RNA-binding sites whose combined activity is essential for function, revealing that eIF4G itself contributes to mRNA engagement and directional unwinding specificity.

    Evidence Systematic truncation/point mutagenesis of yeast eIF4G1 RNA-binding domains with in vitro RNA-binding and in vivo growth assays; later, helicase substrate-specificity assays

    PMID:12810920 PMID:22467875

    Open questions at the time
    • Whether mammalian eIF4G1 RNA-binding domains show identical specificity not tested
    • Structural basis of 5'-overhang preference not resolved
  7. 2006 High

    The eIF4G–eIF3 interface was mapped to eIF3 subunit e (with later refinement to subunits c/d/e), and mTOR signaling was shown to stimulate this interaction up to fivefold via rapamycin-sensitive phosphorylation, identifying a new regulatory step in translation initiation distinct from 4E-BP control.

    Evidence Mass spectrometry of proteolyzed eIF3–eIF4G complex, competition binding, co-IP with rapamycin/wortmannin inhibition, fluorescence anisotropy and site-specific cross-linking

    PMID:16541103 PMID:16766523 PMID:24092755

    Open questions at the time
    • Identity of the specific phosphorylation site(s) on eIF4G or eIF3 mediating mTOR-dependent association not identified
    • Whether mTOR acts directly or through an intermediate kinase unclear
  8. 2005 High

    Stress-responsive kinase Pak2 was identified as a direct eIF4G kinase at S896 that inhibits cap-dependent translation, establishing a mechanism for translational repression under growth-arrest conditions independent of 4E-BP.

    Evidence In vitro kinase assay, phosphomutant reconstitution in eIF4G-depleted lysate, RNAi rescue

    PMID:16281055

    Open questions at the time
    • Whether S896 phosphorylation occurs during specific physiological stresses in vivo not demonstrated
    • Structural consequence of S896 phosphorylation on eIF4G conformation unknown
  9. 2010 High

    The mechanism of eIF4A activation by eIF4G was resolved at the conformational level: bipartite eIF4G contacts induce a half-open eIF4A conformation that pre-aligns helicase motifs and accelerates rate-limiting phosphate release.

    Evidence FRET-based conformational assays, interface mutagenesis, ATPase kinetics

    PMID:21062831

    Open questions at the time
    • Whether this mechanism applies to mammalian eIF4A1 vs. eIF4A2 equally not tested
    • No high-resolution structure of the full eIF4G–eIF4A complex
  10. 2011 High

    Missense mutations in EIF4G1 were linked to familial Parkinson's disease: p.Ala502Val disrupts eIF4E binding and p.Arg1205His disrupts eIF3e binding, with mutant-expressing cells showing increased ROS vulnerability, establishing eIF4G1 as a PD susceptibility gene.

    Evidence Genome-wide linkage, Sanger sequencing, co-IP of mutant proteins, ROS sensitivity assays; later genetic epistasis with VPS35 and α-synuclein across yeast/worm/mouse

    PMID:21907011 PMID:25533483

    Open questions at the time
    • Independent replication of PD linkage has yielded mixed results in other cohorts
    • Mechanism linking impaired eIF4F assembly to dopaminergic neuron vulnerability not established
    • Whether translational targets downstream of mutant eIF4G1 drive neurodegeneration is unknown
  11. 2012 High

    eIF4G was established as a scaffold for translational repressors: yeast RGG-domain proteins (Scd6, Npl3, Sbp1) and human DDX3 each bind eIF4G directly to modulate mRNA-specific translation, revealing that eIF4G integrates both activating and repressive signals.

    Evidence Direct binding assays with RGG-domain mutants, translation repression assays in yeast; co-IP of DDX3 with eIF4G/PABP, toeprinting on structured mRNAs

    PMID:22284680 PMID:22872150

    Open questions at the time
    • Whether RGG-mediated repression occurs in mammals not shown
    • Structural basis of the DDX3/eIF4G interface not resolved
  12. 2013 High

    Cdk1:cyclin B was identified as the mitotic kinase that phosphorylates eIF4G1 at Ser1232, enhancing eIF4A binding while reducing RNA association, thus providing a direct mechanism for mitotic translational suppression.

    Evidence Phosphoproteomics, in vitro phosphorylation with recombinant Cdk1:cyclin B, kinase depletion-reconstitution, RNA-binding assays

    PMID:24248602

    Open questions at the time
    • Whether Ser1232 phosphorylation affects specific mRNA subsets in mitosis not determined
    • How reduced RNA binding is compatible with enhanced eIF4A binding structurally is unexplained
  13. 2018 High

    eIF4G1 was shown to exist in two mutually exclusive complexes — with eIF4E (promoting TISU-element cap-proximal initiation) or with eIF1 (promoting scanning) — resolving how a single scaffold supports two distinct modes of initiation site selection.

    Evidence Co-IP of endogenous complexes, eIF1 binding-deficient mutant, TISU reporter assays, leaky scanning assays

    PMID:29987188

    Open questions at the time
    • Structural basis for mutual exclusivity of eIF4E and eIF1 binding not determined
    • Genome-wide identification of mRNAs preferentially translated by each complex not performed
  14. 2020 High

    A neuron-specific microexon in EIF4G1 was shown to function as a translational brake; its CRISPR deletion caused ribosome stalling, upregulation of synaptic proteins, stress granule coalescence, and behavioral/cognitive deficits in mice, linking alternative splicing of eIF4G1 to neural circuit function.

    Evidence CRISPR-Cas9 microexon deletion, ribosome profiling, proteomics, granule imaging, mouse behavioral and electrophysiological testing

    PMID:31999954

    Open questions at the time
    • Molecular mechanism by which the microexon causes ribosome stalling is not defined
    • Whether microexon loss contributes to human autism spectrum disorder not tested in patient samples
    • Identity of specific mRNAs whose stalling is microexon-dependent not fully catalogued

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the full-length structure of mammalian eIF4G1 and how it dynamically reconfigures among its multiple partner complexes, the identity of specific mRNA targets whose dysregulated translation drives neurodegeneration in EIF4G1-mutant Parkinson's disease, and the in vivo significance of proteasomal eIF4G cleavage in translational remodeling.
  • No full-length eIF4G1 structure available
  • Translational targets downstream of PD-linked mutations not identified
  • Physiological role of 20S proteasome cleavage of eIF4G in vivo not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0045182 translation regulator activity 6 GO:0060090 molecular adaptor activity 6 GO:0003723 RNA binding 3 GO:0005198 structural molecule activity 3
Localization
GO:0005829 cytosol 4 GO:0005840 ribosome 3
Pathway
R-HSA-392499 Metabolism of proteins 7 R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-5357801 Programmed Cell Death 1
Partners
DDX3XEIF1EIF3EEIF4A1EIF4EMKNK1PABPC1PAK2
Complex memberships
eIF4FeIF4G1–eIF1 scanning complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 4E-BP1 inhibits cap-dependent translation by competing with eIF4G (p220) for binding to eIF4E; a shared 12-amino-acid motif in eIF4G and 4E-BPs mediates this interaction with eIF4E, and 4E-BP1 mutants deficient in eIF4E binding neither displace p220 nor repress translation. Competitive binding assays, deletion/point mutagenesis of eIF4G and 4E-BP1, in vitro translation inhibition assays, 48S pre-initiation complex formation assays The EMBO journal / Molecular and cellular biology High 7651417 8521827
1996 Yeast eIF4G (Tif4632p) physically associates with the poly(A)-binding protein Pab1p; the Pab1p-binding site was mapped to a 114-amino-acid region just proximal to the eIF4E-binding site, and Pab1p binds this region only when complexed to poly(A), providing a molecular bridge between the mRNA cap and poly(A) tail. Co-purification, co-immunoprecipitation, recombinant protein binding assays with deletion mapping The EMBO journal High 9003792
1987 Poliovirus proteinase 2A induces cleavage of the eIF4G subunit p220 of eIF4F; translation of 2A-encoding RNA in vitro was sufficient to cause p220 cleavage, and anti-2A antibodies blocked this activity, establishing 2A as the viral factor triggering p220 proteolysis. In vitro translation of synthetic RNAs encoding 2A, linker insertion/deletion mutagenesis of 2A, antibody inhibition assays, in vitro cleavage assays Journal of virology High 3039165
1999 Human eIF4G recruits the kinase Mnk1 to the eIF4F complex via its C-terminal region, enabling Mnk1 to phosphorylate eIF4E on Ser209; an eIF4E mutant lacking eIF4G-binding capability showed severely impaired phosphorylation in cells, demonstrating that eIF4G provides a docking platform for Mnk1-mediated eIF4E phosphorylation. Co-immunoprecipitation, in vitro kinase assays, cell-based phosphorylation assays with eIF4E binding mutants, p97 interaction studies The EMBO journal High 9878069
1997 Insulin stimulates protein synthesis in skeletal muscle by inducing a ~12-fold increase in the amount of eIF4G bound to eIF4E; this enhanced association is partly attributable to insulin-induced phosphorylation of the translational repressor PHAS-I (4E-BP1), which releases eIF4E for eIF4G binding. m7GTP-Sepharose cap-binding pulldown, quantitative immunoblotting in perfused rat hindlimb, phosphorylation state analysis The American journal of physiology High 9124320
2000 The central region of eIF4GI (aa 613–1090) binds eIF3, eIF4A, and the EMCV IRES; association with eIF4A increases eIF4GI affinity for the EMCV IRES by ~100-fold, and mutants defective in eIF4A binding cannot support 48S complex formation even if IRES binding is intact, indicating that the eIF4G–eIF4A complex (not eIF4G alone) is required for internal ribosomal entry. Mutational analysis, UV cross-linking, filter retention binding assays, in vitro 48S complex formation reconstitution Molecular and cellular biology High 10913184
2001 The X-ray crystal structure of the middle portion of human eIF4GII (2.4 Å) reveals a crescent-shaped HEAT-repeat domain (five HEAT repeats, ten helices); structure-based mutagenesis identified two adjacent surface features that respectively bind eIF4A and the EMCV IRES, and this domain is sufficient for 48S ribosomal complex formation with a picornaviral IRES. X-ray crystallography at 2.4 Å, structure-based site-directed mutagenesis, 48S complex formation assay Molecular cell High 11172724
2000 The eIF4G–PABP interaction is critical for translational control of polyadenylated maternal mRNAs in vertebrates; expression of an eIF4GI mutant defective in PABP binding in Xenopus oocytes reduced translation of polyadenylated mRNA and dramatically inhibited progesterone-induced maturation. Microinjection of eIF4GI PABP-binding mutant into Xenopus oocytes, in vivo translation assays, oocyte maturation assay Current biology High 10996799
2006 eIF4G1 binds directly to eIF3 through the eIF3e (p48/Int-6) subunit; recombinant FLAG-eIF3e competed with intact eIF3 for binding to the eIF3-binding domain of human eIF4G1 in vitro, and overexpression of FLAG-eIF3e in a cell-free system inhibited cap-dependent translation and displaced eIF4G and eIF2α from 40S complexes. Mass spectrometry of proteolyzed eIF3 bound to eIF4G1, competition binding assays with recombinant FLAG-eIF3e, in vitro translation inhibition, polysome analysis The Journal of biological chemistry High 16766523
2006 Insulin activates mTOR to stimulate the association of eIF4G with eIF3 by up to fivefold, independently of eIF4E binding to eIF4G and independently of eIF3 binding to the 40S subunit; this effect is blocked by rapamycin, identifying a novel mTOR-controlled step in translation initiation. Co-immunoprecipitation, pharmacological inhibition (rapamycin, wortmannin), insulin dose-response in cells The EMBO journal High 16541103
2005 Pak2 kinase binds to eIF4G and phosphorylates it (at S896), inhibiting the association of eIF4E with the m7GTP cap and reducing cap-dependent translation; reconstitution with phosphorylated vs. mock-phosphorylated eIF4G confirmed that phosphorylation at this site is responsible for translational inhibition, identifying a stress-activated pathway converging on eIF4G. In vitro kinase assay, eIF4G-depleted reticulocyte lysate reconstitution, site-directed mutagenesis (S896D/S896A), RNAi in contact-inhibited cells, m7GTP pulldown The EMBO journal High 16281055
2008 Neural RNA-binding protein Musashi1 inhibits translation initiation by competing with eIF4G for binding to PABP; deletion of the PABP-interacting domain in Msi1 abolishes translational repression, and Msi1 inhibits 80S (but not 48S) ribosome complex assembly on target mRNAs. Protein co-immunoprecipitation identifying PABP as Msi1 partner, competitive binding assays, in vitro translation/ribosome assembly assays, deletion mutagenesis, immunofluorescence localization to stress granules The Journal of cell biology High 18490513
2010 eIF4G stimulates eIF4A helicase activity by a conformational guidance mechanism: eIF4G binds both domains of eIF4A via a primary (anchoring) and a secondary interface, inducing a 'half-open' conformation that pre-aligns helicase motifs and accelerates the rate-limiting phosphate release step of the ATPase cycle. FRET-based conformational assays, mutagenesis of primary and secondary eIF4G-eIF4A interfaces, ATPase kinetics, solution conformation analysis Nucleic acids research High 21062831
2011 DEAD-box helicase Ded1 (yeast ortholog of DDX3) directly interacts with eIF4G to assemble a Ded1-mRNA-eIF4F complex that stalls in translation initiation and accumulates in stress granules; ATP hydrolysis by Ded1 resolves the stalled complex to allow completion of translation initiation. Co-immunoprecipitation, in vivo and in vitro mRNP assembly assays, stress granule imaging, ATPase-deficient mutant analysis Molecular cell High 21925384
2011 Missense mutations in EIF4G1 (p.Ala502Val, p.Arg1205His, and others) segregate with familial Parkinson's disease; p.Ala502Val disrupts eIF4E binding and p.Arg1205His disrupts eIF3e binding by the mutant eIF4G1 protein (the wild-type protein does not show this disruption), and mutant-expressing cells are more vulnerable to reactive oxygen species. Genome-wide linkage analysis, Sanger sequencing, co-immunoprecipitation of mutant vs. wild-type eIF4G1 with eIF4E and eIF3e, ROS sensitivity assays in cells American journal of human genetics High 21907011
2012 RGG-domain protein Scd6 (yeast) represses translation by directly binding the eIF4G subunit of eIF4F via its RGG domain, forming a translation-repressed mRNP; two other yeast RGG-domain proteins, Npl3 and Sbp1, similarly bind eIF4G directly and repress translation via their RGG motifs, identifying eIF4G as a scaffold for recruitment of translation repressors. Co-purification with eIF4E/eIF4G, direct binding assays with RGG-domain deletion mutants, in vivo translation repression assays Molecular cell High 22284680
2013 Human eIF4G binds eIF3 through a ~90-amino-acid domain that contacts eIF3 subunits -c, -d, and -e simultaneously; site-specific cross-linking revealed two distinct eIF3-binding subdomains within the eIF4G eIF3-binding domain, both of which are required for efficient mRNA recruitment to the ribosome in an eIF4G-dependent translation assay. Fluorescence anisotropy binding assays, site-specific cross-linking with multiple linker positions, eIF4G-dependent in vitro translation assay with subdomain deletion mutants The Journal of biological chemistry High 24092755
2013 Cdk1:cyclin B phosphorylates eIF4G1 at Ser1232 during mitosis; this phosphorylation enhances eIF4A interactions with HEAT domain 2 of eIF4G1 while decreasing association of the eIF4G1/eIF4A complex with RNA, implicating this modification in the mitotic suppression of translation initiation. Phosphoproteomics of interphase vs. nocodazole-arrested mitotic cells, kinase inhibition assays, in vitro phosphorylation with recombinant Cdk1:cyclin B, kinase depletion-reconstitution, RNA-binding assays Molecular and cellular biology High 24248602
2014 Genetic interaction between Parkinson's disease genes VPS35 and EIF4G1 was established; EIF4G1 upregulation causes protein misfolding defects, sortilin (downstream of VPS35) rescues these defects, and interactions converge on α-synuclein pathobiology, conserved from yeast to worm to mouse neurons. Yeast genetic interaction screens, C. elegans and mouse transgenic models, epistasis analysis, sortilin rescue assays, α-synuclein toxicity assays Neuron High 25533483
2014 The small molecule 4EGI-1 inhibits the eIF4E–eIF4G interaction allosterically: crystallography and NMR show it binds a hydrophobic pocket on eIF4E (between β-sheet2 and α-helix1) distant from the eIF4G-binding epitope, causing conformational changes in the H78-L85 region that unfold a short 310-helix and extend α-helix1, displacing eIF4G. X-ray crystallography of eIF4E–4EGI-1 complex, NMR chemical-shift mapping, in vitro and in-cell translation inhibition assays Proceedings of the National Academy of Sciences High 25049413
2012 DDX3 promotes translation of structured mRNAs by clamping onto the eIF4F complex through simultaneous interactions with eIF4G and PABP; DDX3's requirement is specific to selected transcripts with secondary structures near the 5' cap, cannot be substituted by eIF4A, and acts prior to 43S scanning. Co-immunoprecipitation with eIF4G and PABP, competition assays with dominant-negative DDX3 mutants, toeprinting/48S complex formation assays on structured viral and cellular mRNAs The EMBO journal High 22872150
2000 Adenovirus 100k protein binds the C-terminal region of eIF4G (the same region bound by Mnk1) in vivo and in vitro, displacing Mnk1 from eIF4G during infection; this prevents eIF4E phosphorylation and selectively inhibits translation of capped cellular mRNAs while permitting viral late mRNA translation. In vivo and in vitro co-immunoprecipitation, purified eIF4F complex incubation with 100k protein, temperature-sensitive 100k mutant virus experiments, eIF4E phosphorylation assays The EMBO journal High 10880459
2003 Yeast eIF4G1 binds single-stranded RNA through three distinct sites: the N-terminus (aa 1–82), a middle RS-rich domain (aa 492–539), and a C-terminal RS-rich domain (aa 883–952); mutation of arginine residues in the middle RS site abolishes its RNA-binding activity, and deletion of any two sites strongly impairs eIF4G1 function in vitro and in vivo. RNA-binding assays with truncation and point mutants of recombinant eIF4G1, yeast growth assays, in vitro translation assays RNA High 12810920
2004 The 20S proteasome endoproteolytically cleaves eIF4G (a subunit of eIF4F) as well as eIF3a; cleavage of eIF4G differentially alters assembly of ribosomal pre-initiation complexes on different cellular and viral mRNAs, and proteasome inhibitors prevented eIF4G cleavage and restored ribosomal complex assembly in vitro and in vivo. In vitro cleavage assays with purified 20S proteasome, ribosomal complex assembly with pure components, proteasome inhibitor treatments in cells and in vitro Molecular cell High 15546617
1998 During Fas/CD95-induced apoptosis in Jurkat cells, caspases cleave eIF4G, leading to inhibition of protein synthesis; caspase inhibitors (zVAD.FMK, zDEVD.FMK) prevented both eIF4G cleavage and translational inhibition, establishing caspase-dependent eIF4G proteolysis as part of the apoptotic translation shutdown. Immunoblotting for eIF4G cleavage, protein synthesis measurement, pharmacological caspase inhibition, Fas/CD95 receptor activation in Jurkat cells FEBS letters Medium 9821956
2010 Multiple elements in the N-terminal domain of yeast eIF4G1 contribute to eIF4G1•PABP•mRNA complex formation in vivo: the PABP-binding domain, an RNA-binding region (RNA1), and two conserved elements (Box1 and Box2) have overlapping functions; RNA1 and Box1 additionally promote PABP binding by the eIF4G1 NTD, showing that PABP-eIF4G association is one of several redundant interactions stabilizing the eIF4F-mRNA complex. In vivo RNA-dependent PABP-eIF4G co-immunoprecipitation from cell extracts, in vitro RNA-binding and PABP-binding assays with domain deletion mutants, yeast growth assays The EMBO journal High 21139564
2012 RNA unwinding by yeast eIF4F has a strong preference for duplexes with 5'-single-stranded overhangs over 3'-overhangs or blunt ends; this 5'-end specificity is conferred by the RNA-binding domains of eIF4G1 (which promote unwinding of 5'-overhang substrates and inhibit unwinding of 3'-overhang substrates), providing a second mechanism—beyond eIF4E-cap interaction—for directing 43S PIC binding to mRNA 5' ends. RNA unwinding assays with purified eIF4F and eIF4G1 deletion constructs, substrate specificity analysis with 5'- and 3'-overhang duplexes The Journal of biological chemistry High 22467875
2014 Insulin receptor signaling in pancreatic β-cells regulates carboxypeptidase E (CPE) expression via eIF4G1; disruption of insulin receptor expression reduces CPE through inhibition of the eIF4G1 translation initiation scaffold, mediated by transcription factors Pdx1 and SREBP1, leading to impaired proinsulin processing. Conditional insulin receptor knockout in β-cells, CPE and eIF4G1 protein/mRNA analysis, Pdx1/SREBP1 transcription factor studies, rescue experiments with IR or CPE re-expression Proceedings of the National Academy of Sciences Medium 24843127
2015 SBI-0640756 (SBI-756) is a small molecule that directly targets eIF4G1 and disrupts eIF4F complex assembly independently of mTOR; it attenuates growth of BRAF-resistant melanomas in vitro and delays tumor onset in an Nras/Ink4a mouse melanoma model in vivo. Target identification binding assay for SBI-756 on eIF4G1, eIF4F complex co-immunoprecipitation, cell viability and tumor growth assays, in vivo mouse melanoma model Cancer research Medium 26603897
2017 Translation initiation factor eIF4G1 binds preferentially to oligo-uridine motifs in yeast mRNA 5' transcript leaders; yeast eIF4G1 shows intrinsic RNA sequence preferences for oligo(U) in vitro, mRNAs with oligo(U) TL motifs are enriched in eIF4G1 immunoprecipitations, and ribosome profiling following eIF4G1 depletion shows preferentially reduced translation of mRNAs with long TLs including oligo(U)-containing transcripts. In vitro RNA-binding assays to determine sequence preferences, eIF4G1 RNA immunoprecipitation, ribosome profiling after eIF4G1 depletion in yeast RNA High 28546148
2018 eIF4G1 exists in two mutually exclusive complexes in cells: one with eIF4E (promoting TISU-element-dependent, cap-proximal translation initiation) and one with eIF1 (promoting ribosomal scanning and leaky scanning); the eIF1-binding site on eIF4G1 is also indirectly used by eIF4E, and eIF4E-eIF4G1 antagonizes the scanning promoted by eIF1-eIF4G1. Co-immunoprecipitation of endogenous complexes, eIF1 mutant impaired in eIF4G1 binding, TISU element reporter assays, mapping of eIF1-binding site on eIF4G1, leaky scanning assays Molecular and cellular biology High 29987188
2020 Neuronal microexons in eIF4G1 (and eIF4G3), whose splicing is activity-dependent and disrupted in autism, function as a translational brake; CRISPR deletion of the eIF4G1 microexon selectively upregulates synaptic proteins controlling neuronal activity, causes ribosome stalling, and promotes coalescence of cytoplasmic granule components including FMRP; mice lacking the Eif4g1 microexon display social behavior, learning, and memory deficits with altered hippocampal synaptic plasticity. CRISPR-Cas9 microexon deletion, ribosome profiling, proteomics, FMRP interaction assays, granule imaging, mouse behavioral testing and electrophysiology Molecular cell High 31999954
1993 Hyperphosphorylation of p220 (eIF4G) and eIF4E by okadaic acid treatment increases the amount of p220 bound to m7GTP cap structures; eIF4G undergoes both serine and threonine phosphorylation in cells, and hyperphosphorylation of eIF4G recruits more p220 into the cap-associated protein complex. Metabolic 32P labeling, m7GTP-Sepharose pulldown, two-dimensional tryptic phosphopeptide mapping, okadaic acid treatment of HepG2 cells The Journal of biological chemistry Medium 8444875
2008 c-Myc directly activates transcription of all three eIF4F subunits (eIF4E, eIF4AI, and eIF4GI) through canonical E-boxes in their promoters; increased eIF4F levels in turn stimulate c-Myc mRNA translation specifically, forming a feedforward loop linking transcription and translation that contributes to Myc-driven cell proliferation. ChIP for c-Myc at eIF4F subunit promoters, luciferase reporter assays with E-box mutations, MycER activation, quantitative RT-PCR for c-Myc translation, polysome profiling, in vivo lymphoma model Cancer research High 18593934
2016 EIF4G1 interacts directly with ubiquitin-specific protease 10 (USP10) in NSCLC cells; USP10 acts as a negative regulator of EIF4G1-mediated functions, and stable shRNA knockdown of EIF4G1 inhibits NSCLC cell proliferation, anchorage-independent growth, migration, invasion, and induces apoptosis and G0/G1 arrest. Co-immunoprecipitation identifying USP10 as EIF4G1 partner, stable shRNA knockdown, proliferation/apoptosis/invasion assays Oncotarget Medium 27003362

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Upstream and downstream of mTOR. Genes & development 3419 15314020
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2009 Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 2592 19239892
1999 eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annual review of biochemistry 1748 10872469
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 A probability-based approach for high-throughput protein phosphorylation analysis and site localization. Nature biotechnology 1336 16964243
2009 Defining the human deubiquitinating enzyme interaction landscape. Cell 1282 19615732
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1994 Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5'-cap function. Nature 1085 7935836
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
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