Affinage

EEF2

Elongation factor 2 · UniProt P13639

Length
858 aa
Mass
95.3 kDa
Annotated
2026-06-09
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

eEF2 is the translocase GTPase of eukaryotic translation elongation, catalyzing the GTP-dependent shift of the mRNA-tRNA complex from the ribosomal A site to the P site (PMID:2753158); in reconstituted mammalian systems it also drives reverse translocation, and in both directions catalysis depends on domain IV-ribosome contacts (PMID:29453282). Structural work has resolved how these movements occur: cryo-EM of the 80S·eEF2 complex revealed large ratchet-like subunit rearrangements coupled to domain III contacts with the sarcin-ricin loop (PMID:14976550), and comparison of pre- and post-GTP-hydrolysis states using ADP-ribosylated eEF2 as a fiducial showed that GTP hydrolysis induces eEF2 conformational changes sufficient to uncouple the mRNA-tRNA complex from the decoding-center bases A1492/A1493, supporting a two-step model of ratcheting followed by hydrolysis-driven displacement (PMID:17446867). eEF2 activity is gated principally by phosphorylation: the Ca2+/calmodulin-dependent eEF2 kinase phosphorylates eEF2 at Thr56, completely inactivating it and blocking the translocation step, with activity restored by phosphatase dephosphorylation (PMID:3386756, PMID:2753158). This eEF2K-eEF2 axis integrates diverse upstream signals — CDK1-cyclin B and SAPK4/p38δ phosphorylation that inactivates eEF2K (PMID:11500363, PMID:18337751), CDK2-cyclin A phosphorylation of eEF2 itself at Ser595 that recruits eEF2K to promote Thr56 phosphorylation (PMID:23184662), and TGFβ-Erk1/2-p90Rsk signaling and contraction-induced Ca2+/calmodulin inputs that tune elongation rate during growth and muscle work (PMID:20837011, PMID:19188248). eEF2 carries a unique diphthamide residue, the essential ADP-ribosylation target of diphtheria toxin and Pseudomonas exotoxin A, and a single substitution adjacent to it confers toxin resistance (PMID:2887567); structural analysis of the exotoxin A-eEF2 complex shows the diphthamide spans the catalytic cleft to trigger NAD+ cleavage, with toxin recognition mimicking ribosomal nucleotide contacts (PMID:16107839), while diphthamide loss impairs translational fidelity and is required for normal vertebrate development (PMID:18765564, PMID:30335802). Through phosphorylation-controlled elongation, eEF2 mediates translational reprogramming under ribosomal stress (PMID:25332393, PMID:34895463) and gates protein-synthesis-dependent synaptic plasticity, memory, and behavior in neurons (PMID:19823585, PMID:33662272, PMID:35993189). eEF2 additionally serves as a regulatory hub bound by trans-acting factors — CPEB2 dampens its ribosomal GTP hydrolysis to repress HIF-1α mRNA elongation (PMID:22157746), PQBP1 binds non-phosphorylated eEF2 to block Thr56 phosphorylation (PMID:33662272), and LDHA sequesters eEF2 from ribosomes in an NADH-dependent manner (PMID:35176139).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1989 High

    Established the precise elongation step eEF2 executes and how phosphorylation shuts it off, defining the molecular basis of elongation control.

    Evidence In vitro translation and puromycin-reactivity translocation assays with phosphatase reactivation in cell-free systems

    PMID:2753158 PMID:3386756

    Open questions at the time
    • Did not resolve the structural transitions underlying translocation
    • The full upstream signaling that controls eEF2K was not yet mapped
  2. 1987 High

    Identified diphthamide as the essential ADP-ribosylation target on eEF2 exploited by bacterial toxins, linking a unique modified residue to toxin sensitivity.

    Evidence cDNA cloning of a toxin-resistant variant and transfection into mouse L cells with cell-free ADP-ribosylation assay

    PMID:2887567

    Open questions at the time
    • The endogenous cellular function of diphthamide was not addressed
    • Structural basis of toxin recognition not yet known
  3. 2005 High

    Resolved how toxins recognize and chemically attack the diphthamide, explaining universal eEF2 targeting through ribosome mimicry.

    Evidence Four X-ray crystal structures of the Pseudomonas exotoxin A-eEF2 complex with a non-hydrolysable NAD+ analogue

    PMID:16107839

    Open questions at the time
    • Did not address physiological diphthamide function
    • Translocation mechanism on the ribosome addressed by separate structures
  4. 2007 High

    Defined the conformational logic of translocation, showing GTP hydrolysis drives tRNA-mRNA displacement after eEF2 binding induces ribosomal ratcheting.

    Evidence Cryo-EM of 80S·eEF2 (sordarin-stalled) and of ADP-ribosylated eEF2 before/after GTP hydrolysis

    PMID:14976550 PMID:17446867

    Open questions at the time
    • Atomic-resolution intermediate states not fully resolved
    • Coupling of phosphorylation to these conformational steps not structurally shown
  5. 2008 High

    Mapped the signaling network converging on eEF2K to set elongation rate, connecting cell-cycle and stress kinases to eEF2 phosphorylation.

    Evidence In vitro kinase assays plus cell-based epistasis (dominant-negative, mass-fingerprinting) for SAPK4/p38δ and CDK1-cyclin B on eEF2K Ser359

    PMID:11500363 PMID:18337751

    Open questions at the time
    • Quantitative contribution of each kinase in vivo not resolved
    • Cross-talk among parallel inputs not defined
  6. 2012 High

    Showed eEF2 itself can be phosphorylated to recruit eEF2K, revealing a feed-forward layer where CDK2 priming promotes inhibitory Thr56 phosphorylation.

    Evidence In vitro CDK2-cyclin A kinase assay on eEF2 Ser595 with S595A mutagenesis and cell-cycle phospho-analysis

    PMID:23184662

    Open questions at the time
    • Structural basis of eEF2K recruitment to phospho-Ser595 not defined
    • Physiological extent of cell-cycle elongation control not quantified
  7. 2010 Medium

    Extended eEF2K regulation to growth-factor and contractile signaling, showing TGFβ-Erk-p90Rsk and Ca2+/calmodulin inputs tune eEF2 activity in tissue contexts.

    Evidence Dominant-negative p90Rsk and kinase inhibitors in mesangial cells; eEF2K inhibition and kinase-dead AMPK in ex vivo muscle

    PMID:19188248 PMID:20837011

    Open questions at the time
    • AMPK-independent contraction signaling only partially accounts for synthesis suppression
    • Single-lab tissue models
  8. 2011 Medium

    Placed eEF2 within the broader elongation machinery and as a target of trans-acting translational repressors, expanding its role beyond bulk translocation.

    Evidence Yeast genetic epistasis with eIF5A; Co-IP and in vitro GTP hydrolysis/transit-time assays for CPEB2 repression of HIF-1α mRNA

    PMID:21822730 PMID:22157746

    Open questions at the time
    • Structural mode of CPEB2-eEF2 inhibition unknown
    • Generality of mRNA-selective elongation repression unclear
  9. 2014 Medium

    Defined two post-translational modification layers of eEF2 — Lys525 trimethylation by FAM86A and a Csk tyrosine phosphorylation that triggers nuclear translocation of a cleaved fragment — linking eEF2 modifications to fidelity and to non-translational nuclear effects.

    Evidence In vitro methyltransferase and kinase assays; yeast genetics (frameshifting, sordarin sensitivity); SUMO-dependent localization and fragment overexpression

    PMID:24648518 PMID:25231979

    Open questions at the time
    • Functional reader/role of Lys525 methylation in mammals not established
    • Physiological significance of nuclear eEF2 fragments uncertain
  10. 2018 Medium

    Demonstrated eEF2 catalyzes reverse translocation requiring domain IV-ribosome contacts, and that diphthamide supports translocation fidelity, unifying the catalytic and modification roles.

    Evidence Reconstituted mammalian translation with ADP-ribosylation and GTP analogues; yeast dphΔ/eft2Δ epistasis with frameshifting and drug-sensitivity readouts

    PMID:29453282 PMID:30335802

    Open questions at the time
    • Physiological occurrence of reverse translocation unclear
    • Identity of fidelity-critical transcripts requiring diphthamide unknown
  11. 2022 High

    Connected eEF2-controlled elongation to synaptic plasticity and behavior, and to translational reprogramming and tumor suppression under ribosomal stress.

    Evidence PQBP1- and Eef2-mutant mice with electrophysiology, SUnSET, polysome profiling, chemogenetic/pharmacological rescue; Rpl24-eEF2K double-mutant colorectal cancer model

    PMID:25332393 PMID:33662272 PMID:34895463 PMID:35993189

    Open questions at the time
    • Transcript selectivity of stress-induced reprogramming not fully defined
    • Circuit-level mechanism linking elongation rate to behavior incomplete
  12. 2024 Medium

    Identified eEF2 as a reader of ac4C-modified mRNA and a target of metabolic sequestration, broadening its regulatory inputs to RNA modification and redox state.

    Evidence RIP/RNA pulldown/ribosome profiling for ac4C reading; Co-IP and Ldha knockout with NADH manipulation for LDHA sequestration

    PMID:35176139 PMID:39030964

    Open questions at the time
    • Structural basis of eEF2 ac4C recognition unknown
    • Single-lab findings awaiting independent confirmation

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream inputs (cell-cycle, growth-factor, stress, metabolic, RNA-modification) are integrated quantitatively to set elongation rate on specific transcripts in vivo remains unresolved.
  • No unified quantitative model of competing eEF2 regulatory inputs
  • Transcript-specific elongation control mechanisms not mapped
  • Atomic structures coupling phosphorylation state to translocation conformations lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0045182 translation regulator activity 2 GO:0140098 catalytic activity, acting on RNA 2 GO:0003723 RNA binding 1
Localization
GO:0005840 ribosome 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1643685 Disease 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CDK2CPEB2EEF2KLDHANAT10PQBP1
Complex memberships
80S ribosome elongation complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Phosphorylation of EF-2 by the Ca2+/calmodulin-dependent EF-2 kinase completely inactivates it in poly(U)-directed translation; phosphorylated EF-2 inhibits non-phosphorylated EF-2, and dephosphorylation by phosphatase restores activity, establishing phosphorylation as a direct mechanism of translational elongation control. In vitro translation assay (poly(U)-directed polyphenylalanine synthesis), phosphatase treatment/reactivation Nature High 3386756
1989 Phosphorylated eEF2 is unable to promote the shift of aminoacyl(peptidyl)-tRNA from the A site to the P site (translocation), establishing that phosphorylation specifically blocks the translocation step of elongation. Puromycin reactivity assay measuring A-to-P site tRNA translocation in cell-free system FEBS letters High 2753158
2004 Cryo-EM structure of the yeast 80S·eEF2·sordarin complex at 11.7 Å revealed large conformational changes in eEF2 and the ribosome, including ratchet-like subunit rearrangement (RSR); sordarin positions domain III of eEF2 to interact with the sarcin-ricin loop of 25S rRNA and rpS23, stalling eEF2 in a GTPase activation-like state and suggesting the RSR is part of the tRNA translocation mechanism. Cryo-EM single-particle reconstruction; molecular interpretation of domain movements The EMBO journal High 14976550
2005 Crystal structures of a catalytically active complex between Pseudomonas exotoxin A (ETA) and eEF2 revealed that the diphthamide residue (modified His) of eEF2 spans a cleft and faces the two phosphates and a ribose of the NAD+ analogue, indicating diphthamide triggers NAD+ cleavage and interacts with the oxacarbenium intermediate; the toxin-bound phosphates mimic nucleotides in a 18S rRNA conformational switch, explaining ribosome mimicry for universal eEF2 recognition. X-ray crystallography (four structures of ETA–eEF2 complex with non-hydrolysable NAD+ analogue betaTAD) Nature High 16107839
2007 Cryo-EM reconstructions of eukaryotic ribosomes complexed with ADP-ribosylated eEF2 (ADPR-eEF2) before and after GTP hydrolysis showed that GTP hydrolysis induces conformational changes in eEF2 sufficient to uncouple the mRNA-tRNA complex from two conserved bases in the ribosomal decoding center (A1492/A1493), supporting a two-step translocation model in which eEF2 binding induces ratcheting and GTP hydrolysis drives tRNA-mRNA displacement. Cryo-EM reconstruction using ADP-ribosylated eEF2 as structural marker; comparison of pre- and post-GTP hydrolysis states The EMBO journal High 17446867
1987 A single G-to-A transition at codon 717 (changing the residue adjacent to the diphthamide-modified His715) confers resistance to diphtheria toxin and Pseudomonas exotoxin A ADP-ribosylation; transfection of this cDNA into mouse L cells confirmed the mutation is sufficient for toxin resistance, establishing diphthamide as the essential ADP-ribosylation target on eEF2. cDNA cloning of toxin-resistant mutant; transfection into mouse L cells; cell-free ADP-ribosylation assay The Journal of biological chemistry High 2887567
2001 SAPK4/p38δ phosphorylates eEF2 kinase (eEF2K) at Ser359 in vitro, causing eEF2K inactivation and consequent eEF2 dephosphorylation (activation); this phosphorylation is also induced in cells by anisomycin and IGF-1 and is blocked by a dominant-negative SAPK4/p38δ mutant, placing SAPK4/p38δ as an upstream inhibitor of eEF2K in the stress and growth-factor signaling pathway. In vitro kinase assay; substrate purification from skeletal muscle extract; cell-based phosphorylation with dominant-negative kinase overexpression The EMBO journal High 11500363
2008 Cdc2 (CDK1)-cyclin B phosphorylates eEF2K at Ser359 in vitro and in vivo; cdc2 activity against Ser359 peaks in mitosis coinciding with low eEF2 phosphorylation, indicating that CDK1-mediated inactivation of eEF2K keeps eEF2 active during mitosis to permit protein synthesis; amino-acid starvation decreases cdc2 activity against eEF2K while TSC2 loss (mTORC1 activation) increases it. Biochemical purification + tryptic mass fingerprinting; in vitro CDK1-cyclin B kinase assay; cell-cycle-stage-specific phosphorylation analysis The EMBO journal High 18337751
2012 Cyclin A-CDK2 phosphorylates eEF2 at Ser595 in vitro and in vivo; S595 phosphorylation varies during the cell cycle, is required for efficient T56 phosphorylation by eEF2K in vivo, and directly stimulates eEF2 T56 phosphorylation by eEF2K in vitro, suggesting S595 recruits eEF2K to eEF2 — the first known eEF2 modification that regulates its own inhibition by eEF2K. In vitro CDK2-cyclin A kinase assay on eEF2; cell-cycle phosphorylation analysis; site-directed mutagenesis (S595A) Molecular and cellular biology High 23184662
2011 CPEB2 interacts with eEF2 to reduce eEF2/ribosome-triggered GTP hydrolysis in vitro and slows peptide elongation of CPEB2-bound RNA in vivo; under normoxia CPEB2-eEF2 interaction represses HIF-1α mRNA translation at the elongation step, and oxidative stress causes CPEB2 dissociation from HIF-1α mRNA, enabling rapid HIF-1α synthesis. Co-immunoprecipitation of CPEB2-eEF2; in vitro GTP hydrolysis assay; ribosome transit-time assay; RNA-binding and stress-response experiments The EMBO journal High 22157746
2014 FAM86A (eEF2-KMT) trimethylates eEF2 at Lys-525; the yeast orthologue Yjr129c (Efm3) methylates the equivalent Lys-509 in yeast eEF2 in vitro and in vivo; loss of this methylation causes increased -1 frameshifting and hypersensitivity to the eEF2-specific drug sordarin, establishing Lys methylation as a functionally important post-translational modification of eEF2. In vitro methyltransferase assay; yeast genetics (KO phenotype analysis); mass spectrometry to identify methylation site The Journal of biological chemistry High 25231979
2014 HIV-1 Gag interacts with eEF2 via loops in the amino-terminal capsid domain to block stress granule (SG) assembly; cyclophilin A (CypA) stabilizes the Gag-eEF2 association; eEF2 depletion lifts the SG blockade but also impairs virus production and infectivity, and Gag recruits G3BP1 to disassemble preformed SGs by displacing eEF2. Co-immunoprecipitation; RNAi knockdown; stress granule assembly/disassembly imaging; viral infectivity assay Nature communications Medium 25229650
2003 p53 forms a salt-stable cytoplasmic complex with eEF2, confirmed by co-immunoprecipitation, anti-eEF2 antiserum recognition, diphtheria toxin ADP-ribosylation, and GTP photolabeling; the p53-eEF2 complex is found in both polyribosomal and subribosomal fractions; nuclear translocation of p53 decreases eEF2 binding; ts-p53 renaturation selectively alters p53 mRNA (not bulk mRNA) sensitivity to the elongation inhibitor cycloheximide. Co-immunoprecipitation; sucrose gradient sedimentation; ADP-ribosylation by diphtheria toxin; GTP photolabeling; ts-p53 renaturation experiment Journal of cellular physiology Medium 12891704
2002 Crystals of Saccharomyces cerevisiae eEF2 in complex with GDP were obtained and diffract to 2.85 Å, establishing the first purification and crystallization protocol for eukaryotic eEF2 and enabling subsequent structural studies. Protein purification from industrial yeast; vapor-diffusion crystallization; X-ray diffraction Acta crystallographica. Section D, Biological crystallography Medium 11914505
1991 Oxidation of Trp221 in eEF-2 (but not Trp343) by N-bromosuccinimide inactivates its ribosome-dependent GTPase and polyphenylalanine synthesis activities without preventing GTP binding or ribosome·eEF-2·GMPPNP complex formation; oxidized eEF-2 fails to protect ribosomes against ricin inactivation, suggesting Trp221 or its surrounding sequence contacts the GAGA loop of 28S rRNA at the sarcin-ricin site. Chemical modification (N-bromosuccinimide); GTPase and polyphenylalanine synthesis assays; ricin protection assay; ribosome complex formation assay The Journal of biological chemistry Medium 8253723
1998 The U5 snRNP 116-kDa protein, a homologue of ribosomal elongation factor EF-2, forms a stable RNA-free complex with the U5-200kDa RNA unwindase, U5-220kDa (hPrp8), and U5-40kDa (a novel WD-40 protein) as shown by sedimentation analysis of dissociated U5 snRNP; hPrp8 binds simultaneously to the 40-kDa and 116-kDa proteins, positioning the EF-2 homologue within the spliceosomal architecture. Sedimentation analysis of chaotrope-dissociated U5 snRNP; cDNA cloning; biochemical co-fractionation Molecular and cellular biology Low 9774689
1994 eEF2 kinase is bound to Hsp90 as demonstrated by co-adsorption with anti-Hsp90 immunoadsorbents from partly purified kinase preparations and crude reticulocyte lysates, establishing Hsp90 as a chaperone partner of the eEF2K-eEF2 regulatory complex. Immunoadsorption (anti-Hsp90 monoclonal antibody); co-purification from reticulocyte lysate FEBS letters Low 8050573
2001 Geldanamycin (GA) disrupts the EF-2 kinase/Hsp90 protein complex as measured by co-immunoprecipitation, leading to decreased eEF2K protein in cell lysates; overexpression of eEF2K abrogates GA-mediated glioma cell killing, demonstrating that destruction of eEF2K downstream of Hsp90 disruption is a cytotoxic mechanism of GA in glioma. Co-immunoprecipitation; eEF2K overexpression rescue; clonogenic survival assay; xenograft model Cancer research Medium 11358819
2009 Post-training dephosphorylation of eEF2 (activation) occurs within 0.5–2 h in hippocampus and amygdala after fear conditioning; blockade of NMDA receptors impedes this dephosphorylation and memory retention; hippocampus-specific overexpression of eEF2K inhibits protein synthesis and impairs late-phase LTP and long-term hippocampus-dependent memory without affecting short-term memory. Western blot of phospho-eEF2 post-training; NMDA receptor antagonist (MK-801); transgenic overexpression of eEF2K in hippocampus; LTP electrophysiology; behavioral memory tests PloS one Medium 19823585
2008 Diphthamide modification of eEF2 requires the J-domain protein Dph4; cells from Dph4 mutant mouse embryos lack diphthamide on eEF2 and are resistant to diphtheria toxin killing; Dph4-null mice show growth retardation, embryonic lethality, and preaxial polydactyly identical to Dph1 mutants, establishing that diphthamide is required for normal vertebrate development, likely through translational fidelity of specific proteins. Mouse genetics (ENU mutant); diphtheria toxin resistance assay; immunolocalization of Dph4; phenotypic analysis of homozygous mutants Journal of cell science Medium 18765564
2018 eEF2 catalyzes ribosomal reverse translocation (backward by one mRNA triplet) in a reconstituted mammalian translation system; this requires a cognate tRNA in the E-site and cannot occur spontaneously; efficiency increases with eEF2 concentration and non-hydrolyzable GTP analogues; ADP-ribosylation of eEF2 domain IV blocks reverse translocation, establishing domain IV-ribosome interaction as critical for catalysis in both directions. Reconstituted in vitro mammalian translation system; ADP-ribosylation of eEF2 (diphtheria toxin); non-hydrolyzable GTP analogues; measurement of ribosomal reverse translocation The Journal of biological chemistry High 29453282
2014 Ribosomal stress activates the eEF2K-eEF2 pathway, inhibiting translation elongation; this leads to translational reprogramming in which TOP mRNAs (encoding ribosomal proteins and translation factors) are paradoxically recruited onto polysomes, increasing their relative translation while global protein synthesis decreases. Ribosome biogenesis defect models; phospho-eEF2 Western blot; polysome profiling; TOP mRNA-specific translation analysis Nucleic acids research Medium 25332393
2021 PQBP1 binds specifically to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56; PQBP1 loss reduces general protein synthesis by suppressing translational elongation and impairs hippocampal mGluR-LTD and associated behaviors. Co-immunoprecipitation; phospho-eEF2 Western blot; polysome profiling; SUnSET protein synthesis assay; hippocampal LTD electrophysiology; behavioral assays in PQBP1-KO mice Molecular cell High 33662272
2014 C-terminal Src kinase (Csk) phosphorylates eEF2 on a tyrosine residue; this phosphorylation does not affect cytoplasmic translation but promotes proteolytic cleavage of eEF2 and SUMOylation-dependent nuclear translocation of the cleaved fragment; nuclear eEF2 fragments induce nuclear morphological changes and aneuploidy. In vitro kinase assay (Csk on eEF2); co-immunoprecipitation; immunofluorescence nuclear localization; SUMO pathway manipulation; overexpression of eEF2 fragments The Journal of biological chemistry Medium 24648518
2016 During myocardial ischemia-reperfusion, phosphorylated eEF2 is SUMOylated and translocates to the nucleus of cardiomyocytes; eEF2 overexpression upregulates Bcl-2 to reduce apoptosis, while the N-terminal fragment of eEF2 promotes apoptosis, indicating a bidirectional role of eEF2 in cardiomyocyte apoptosis during ischemia-reperfusion. In vivo rat ischemia-reperfusion model; immunocytochemistry; immunofluorescence; Western blot; flow cytometry apoptosis assay; eEF2 fragment transfection Journal of cardiology Low 27401398
2010 TGFβ activates eEF2 (decreases Thr56 phosphorylation) via an Erk1/2-dependent activation of p90Rsk, which phosphorylates and inactivates eEF2K; dominant-negative p90Rsk reverses TGFβ-induced eEF2 dephosphorylation and eEF2K inhibition, and attenuates TGFβ-induced protein synthesis and mesangial cell hypertrophy. Kinase inhibitors (Erk1/2); dominant-negative p90Rsk; phospho-Western blot; protein synthesis measurement; cell hypertrophy assay FEBS letters Medium 20837011
2018 In yeast, loss of diphthamide modification on eEF2 (dphΔ) combined with reduced eEF2 availability (eft2Δ) causes synthetic growth defects, increased -1 ribosomal frameshifting, and hypersensitivity to translation-perturbing drugs (hygromycin, anisomycin), demonstrating that diphthamide on eEF2 is important for translational fidelity of the EF2 translocation function. Yeast genetic analysis (SGA interactions, double mutants); frameshifting reporter assay; drug sensitivity assays; competitive fitness assays PloS one Medium 30335802
2022 Genetic reduction of eEF2 in excitatory neurons of the mouse medial prefrontal cortex (mPFC) reduces protein synthesis, lowers dendritic spine density, reduces excitability, and diminishes AMPAR-mediated synaptic transmission, resulting in defective social novelty behavior and elevated anxiety; chemogenetic activation of mPFC excitatory neurons or AMPAR potentiation rescues the social novelty deficit. Eef2 heterozygous mouse; region-specific viral knockdown; electrophysiology; SUnSET protein synthesis; DREADD chemogenetics; AMPAR potentiator pharmacology; behavioral assays EMBO reports Medium 35993189
2011 eIF5A genetically interacts with eEF2 during translation elongation in yeast: the eIF5A(K56A) hypusine-deficient mutant is synthetically sick with the dominant-negative eEF2(H699K) mutant; high-copy eEF2 suppresses growth, cell-size, protein synthesis, and polysome profile defects of eIF5A(K56A), placing eIF5A and eEF2 in the same elongation pathway. Yeast genetic epistasis (synthetic sickness, high-copy suppression); polysome profiling; protein synthesis measurement; hygromycin B sensitivity assay Amino acids Medium 21822730
2009 In fast-twitch skeletal muscle, inhibition of eEF2K completely blunts the contraction-induced increase in eEF2 phosphorylation and partially (30–40%) blunts the suppression of protein synthesis; the eEF2K activation is downstream of Ca2+/calmodulin but independent of AMPK, as demonstrated by intact protein synthesis suppression in muscles overexpressing kinase-dead AMPK. Ex vivo muscle contraction; eEF2K inhibitor; kinase-dead AMPK overexpression; protein synthesis (ribosome transit time); Ca2+ manipulation The Journal of physiology Medium 19188248
2018 Stm1 (yeast stress protein) stabilizes eEF2 on the 80S ribosome in the GTP-bound form independently of eEF2's diphthamide modification; Stm1 does not inhibit eEF2 GTPase activity during the first GTP hydrolysis round; the core region of Stm1 (aa 47–143) is required for ribosome binding and eEF2 stabilization. Reconstituted yeast cell-free translation system; biochemical analysis of eEF2-ribosome binding in presence of Stm1; Stm1 truncation mutant analysis; GTPase assay Journal of biochemistry Medium 29069440
2024 NAT10-mediated ac4C modification within the coding sequence of HMGB2 mRNA facilitates eEF2 binding to the ac4C sites, enhancing HMGB2 mRNA translation; eEF2 is identified as a reader of ac4C mRNA modifications that promotes translation of ac4C-modified transcripts. RNA immunoprecipitation (RIP); RNA pulldown; mass spectrometry; ribosome profiling; site-specific ac4C mutation; nascent protein synthesis assay Cancer communications Medium 39030964
2021 Rpl24 (ribosomal protein) mutation suppresses translation elongation through phosphorylation of eEF2 (reducing protein synthesis by ~40% in tumour cells), and genetic inactivation of eEF2K in Rpl24 mutant mice completely restores elongation rates and protein synthesis, as well as abolishing tumour suppression in a colorectal cancer model. Rpl24 mutant mouse; eEF2K genetic ablation rescue; polysome profiling; SUnSET protein synthesis assay; colorectal cancer mouse model tumorigenesis assay eLife High 34895463
2022 LDHA interacts with eEF2 in the cytoplasm in an NADH-dependent manner, sequestering eEF2 away from the ribosome; LDHA knockout or NADH-competitive LDHA inhibitors release eEF2, upregulate translation, and enhance megakaryocyte (MK) maturation and platelet production both in vitro and in vivo. Co-immunoprecipitation; MK/platelet-specific Ldha knockout mouse; NADH manipulation; LDHA inhibitor treatment; in vitro MK maturation assay; in vivo platelet count Blood Medium 35176139

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation. Nature 401 3386756
2013 The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 352 23706743
2004 Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation. The EMBO journal 322 14976550
2005 Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. The FEBS journal 274 16098202
2001 A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. The EMBO journal 205 11500363
2011 Eukaryotic elongation factor-2 (eEF2): its regulation and peptide chain elongation. Cell biochemistry and function 172 21394738
2007 Structures of modified eEF2 80S ribosome complexes reveal the role of GTP hydrolysis in translocation. The EMBO journal 152 17446867
2010 Synaptic activity controls dendritic spine morphology by modulating eEF2-dependent BDNF synthesis. The Journal of neuroscience : the official journal of the Society for Neuroscience 134 20427644
1989 Mechanism of elongation factor 2 (EF-2) inactivation upon phosphorylation. Phosphorylated EF-2 is unable to catalyze translocation. FEBS letters 131 2753158
2011 eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition, thereby modulating cytotoxicity of novel Akt inhibitor MK-2206. Cancer research 127 21307130
2021 Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression. Journal of neuroinflammation 126 33526073
1998 The human U5-220kD protein (hPrp8) forms a stable RNA-free complex with several U5-specific proteins, including an RNA unwindase, a homologue of ribosomal elongation factor EF-2, and a novel WD-40 protein. Molecular and cellular biology 124 9774689
2005 Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry. Nature 112 16107839
2008 AMPK activation attenuates S6K1, 4E-BP1, and eEF2 signaling responses to high-frequency electrically stimulated skeletal muscle contractions. Journal of applied physiology (Bethesda, Md. : 1985) 111 18187610
2010 History of myxozoan character evolution on the basis of rDNA and EF-2 data. BMC evolutionary biology 110 20667097
2011 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor. The Journal of biological chemistry 104 22020937
2013 The role of eEF2 pathway in learning and synaptic plasticity. Neurobiology of learning and memory 96 23742918
2009 A Ca(2+)-calmodulin-eEF2K-eEF2 signalling cascade, but not AMPK, contributes to the suppression of skeletal muscle protein synthesis during contractions. The Journal of physiology 88 19188248
2001 Changes in the phosphorylation of initiation factor eIF-2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. Journal of neurochemistry 87 11520898
2001 Disruption of the EF-2 kinase/Hsp90 protein complex: a possible mechanism to inhibit glioblastoma by geldanamycin. Cancer research 85 11358819
2008 cdc2-cyclin B regulates eEF2 kinase activity in a cell cycle- and amino acid-dependent manner. The EMBO journal 84 18337751
2018 Dual Suppressive Effect of miR-34a on the FOXM1/eEF2-Kinase Axis Regulates Triple-Negative Breast Cancer Growth and Invasion. Clinical cancer research : an official journal of the American Association for Cancer Research 77 29748184
2008 The alpha-kinases TRPM6 and TRPM7, but not eEF-2 kinase, phosphorylate the assembly domain of myosin IIA, IIB and IIC. FEBS letters 77 18675813
2014 The translation elongation factor eEF2 is a novel tumor‑associated antigen overexpressed in various types of cancers. International journal of oncology 73 24589652
2012 Phosphorylation of eukaryotic elongation factor 2 (eEF2) by cyclin A-cyclin-dependent kinase 2 regulates its inhibition by eEF2 kinase. Molecular and cellular biology 72 23184662
2014 eEF2 and Ras-GAP SH3 domain-binding protein (G3BP1) modulate stress granule assembly during HIV-1 infection. Nature communications 71 25229650
2010 The channel-kinase TRPM7 regulates phosphorylation of the translational factor eEF2 via eEF2-k. Cellular signalling 71 21112387
2019 Genetic reduction of eEF2 kinase alleviates pathophysiology in Alzheimer's disease model mice. The Journal of clinical investigation 70 30667373
2011 CPEB2-eEF2 interaction impedes HIF-1α RNA translation. The EMBO journal 63 22157746
1991 Purification and properties of extracellular lipase from Pseudomonas aeruginosa EF2. Journal of general microbiology 63 1748875
2009 Overexpression of eukaryotic elongation factor eEF2 in gastrointestinal cancers and its involvement in G2/M progression in the cell cycle. International journal of oncology 62 19360331
2014 IL-6 impairs myogenic differentiation by downmodulation of p90RSK/eEF2 and mTOR/p70S6K axes, without affecting AKT activity. BioMed research international 59 24967341
2008 Skeletal muscle eEF2 and 4EBP1 phosphorylation during endurance exercise is dependent on intensity and muscle fiber type. American journal of physiology. Regulatory, integrative and comparative physiology 59 19036825
2017 eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures. Cerebral cortex (New York, N.Y. : 1991) 57 27005990
2008 Diphthamide modification of eEF2 requires a J-domain protein and is essential for normal development. Journal of cell science 57 18765564
2020 SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy. Cells 56 32059483
2011 Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats. American journal of physiology. Endocrinology and metabolism 55 21917636
2006 A nuclear phylogeny of the Florideophyceae (Rhodophyta) inferred from combined EF2, small subunit and large subunit ribosomal DNA: establishing the new red algal subclass Corallinophycidae. Molecular phylogenetics and evolution 50 17197199
1987 Highly frequent single amino acid substitution in mammalian elongation factor 2 (EF-2) results in expression of resistance to EF-2-ADP-ribosylating toxins. The Journal of biological chemistry 50 2887567
2002 Purification and crystallization of the yeast elongation factor eEF2. Acta crystallographica. Section D, Biological crystallography 47 11914505
2019 MicroRNA-143-5p targeting eEF2 gene mediates intervertebral disc degeneration through the AMPK signaling pathway. Arthritis research & therapy 46 30987676
2018 PRMT7 contributes to the metastasis phenotype in human non-small-cell lung cancer cells possibly through the interaction with HSPA5 and EEF2. OncoTargets and therapy 46 30147338
2014 Identification and characterization of a novel evolutionarily conserved lysine-specific methyltransferase targeting eukaryotic translation elongation factor 2 (eEF2). The Journal of biological chemistry 46 25231979
2020 The role of eEF2 kinase in the rapid antidepressant actions of ketamine. Advances in pharmacology (San Diego, Calif.) 45 32616215
2016 eEF-2 kinase is a critical regulator of Warburg effect through controlling PP2A-A synthesis. Oncogene 43 27181208
2007 Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity. Journal of biochemistry 42 17525101
2016 Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. Proceedings of the National Academy of Sciences of the United States of America 41 27506798
2008 EEF2 analysis challenges the monophyly of Archaeplastida and Chromalveolata. PloS one 41 18612431
2004 5-HT stimulates eEF2 dephosphorylation in a rapamycin-sensitive manner in Aplysia neurites. Journal of neurochemistry 40 15341530
2024 Targeting N4-acetylcytidine suppresses hepatocellular carcinoma progression by repressing eEF2-mediated HMGB2 mRNA translation. Cancer communications (London, England) 39 39030964
2014 Ribosomal stress activates eEF2K-eEF2 pathway causing translation elongation inhibition and recruitment of terminal oligopyrimidine (TOP) mRNAs on polysomes. Nucleic acids research 38 25332393
2002 Thermodynamic activation properties of elongation factor 2 (EF-2) proteins from psychrotolerant and thermophilic Archaea. Extremophiles : life under extreme conditions 37 12013435
2019 Cross Talk between eIF2α and eEF2 Phosphorylation Pathways Optimizes Translational Arrest in Response to Oxidative Stress. iScience 36 31627132
2004 Regulation of translation elongation and phosphorylation of eEF2 in rat pancreatic acini. Biochemical and biophysical research communications 36 15158453
2009 Post-training dephosphorylation of eEF-2 promotes protein synthesis for memory consolidation. PloS one 34 19823585
2020 The eEF2 kinase-induced STAT3 inactivation inhibits lung cancer cell proliferation by phosphorylation of PKM2. Cell communication and signaling : CCS 33 32054489
2019 eEF2 kinase mediated autophagy as a potential therapeutic target for paclitaxel-resistant triple-negative breast cancer. Annals of translational medicine 33 32042799
2011 Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression. Biochemical and biophysical research communications 32 21945617
1996 Localization of ZNF164, ZNF146, GGTA1, SOX2, PRLR and EEF2 on homoeologous cattle, sheep and goat chromosomes by fluorescent in situ hybridization and comparison with the human gene map. Cytogenetics and cell genetics 32 8641144
2015 Bidirectional regulation of eEF2 phosphorylation controls synaptic plasticity by decoding neuronal activity patterns. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 25762683
2021 PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation. Molecular cell 30 33662272
1991 Phosphorylation regulates the activity of the eEF-2-specific Ca(2+)- and calmodulin-dependent protein kinase III. The Journal of biological chemistry 30 1885575
2001 beta-Adrenergic agonists increase phosphorylation of elongation factor 2 in cardiomyocytes without eliciting calcium-independent eEF2 kinase activity. FEBS letters 29 11165254
1979 Ef2: a new LY-3-linked light-chain marker expressed in normal mouse serum immunoglobulin. The Journal of experimental medicine 29 109570
2020 eEF2/eEF2K Pathway in the Mature Dentate Gyrus Determines Neurogenesis Level and Cognition. Current biology : CB 28 32707059
2018 Eukaryotic translation elongation factor 2 (eEF2) catalyzes reverse translocation of the eukaryotic ribosome. The Journal of biological chemistry 28 29453282
2003 Glucose regulates EF-2 phosphorylation and protein translation by a protein phosphatase-2A-dependent mechanism in INS-1-derived 832/13 cells. The Journal of biological chemistry 28 12644453
1981 Sequence diversity within a subgroup of mouse immunoglobulin kappa chains controlled by the IgK-Ef2 locus. The Journal of experimental medicine 28 6788891
2020 MALAT1 Promotes Cell Tumorigenicity Through Regulating miR-515-5p/EEF2 Axis in Non-Small Cell Lung Cancer. Cancer management and research 27 32943920
2017 MYCN amplified neuroblastoma requires the mRNA translation regulator eEF2 kinase to adapt to nutrient deprivation. Cell death and differentiation 27 28574509
2010 Inhibition of eEF2-K by thieno[2,3-b]pyridine analogues. Bioorganic & medicinal chemistry letters 27 20189382
1991 Physiological regulation and optimization of lipase activity in Pseudomonas aeruginosa EF2. Journal of general microbiology 26 1748874
2013 High-throughput screens for eEF-2 kinase. Journal of biomolecular screening 25 24078616
2020 D1 Dopamine Receptor Activation Induces Neuronal eEF2 Pathway-Dependent Protein Synthesis. Frontiers in molecular neuroscience 24 32499677
2018 Importance of diphthamide modified EF2 for translational accuracy and competitive cell growth in yeast. PloS one 24 30335802
2021 Rpl24 mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K. eLife 23 34895463
2012 Carbon monoxide releasing molecule-2 CORM-2 represses global protein synthesis by inhibition of eukaryotic elongation factor eEF2. The international journal of biochemistry & cell biology 23 23041477
2011 eIF5A interacts functionally with eEF2. Amino acids 23 21822730
2003 Cytoplasmic complex of p53 and eEF2. Journal of cellular physiology 23 12891704
2017 Myostatin inhibits eEF2K-eEF2 by regulating AMPK to suppress protein synthesis. Biochemical and biophysical research communications 22 29024627
2020 Circ-EEF2 facilitated autophagy via interaction with mir-6881-3p and ANXA2 in EOC. American journal of cancer research 21 33294264
2017 Modelling mosquito infection at natural parasite densities identifies drugs targeting EF2, PI4K or ATP4 as key candidates for interrupting malaria transmission. Scientific reports 21 29247222
2016 Phosphorylated eEF2 is SUMOylated and induces cardiomyocyte apoptosis during myocardial ischemia reperfusion. Journal of cardiology 21 27401398
2010 TGFβ enforces activation of eukaryotic elongation factor-2 (eEF2) via inactivation of eEF2 kinase by p90 ribosomal S6 kinase (p90Rsk) to induce mesangial cell hypertrophy. FEBS letters 21 20837011
2019 Electroacupuncture Improves Synaptic Function in SAMP8 Mice Probably via Inhibition of the AMPK/eEF2K/eEF2 Signaling Pathway. Evidence-based complementary and alternative medicine : eCAM 20 31641367
2014 C-terminal Src kinase (Csk)-mediated phosphorylation of eukaryotic elongation factor 2 (eEF2) promotes proteolytic cleavage and nuclear translocation of eEF2. The Journal of biological chemistry 20 24648518
1994 Interaction of the calcium and calmodulin regulated eEF-2 kinase with heat shock protein 90. FEBS letters 20 8050573
2020 Repression of eEF2 kinase improves deficits in novel object recognition memory in aged mice. Neurobiology of aging 19 32810756
2016 Coordination of changes in expression and phosphorylation of eukaryotic elongation factor 2 (eEF2) and eEF2 kinase in hypertrophied cardiomyocytes. Biochemistry and biophysics reports 19 28955910
1993 Trp221 is involved in the protective effect of elongation factor eEF-2 on the ricin/alpha-sarcin site of the ribosome. The Journal of biological chemistry 19 8253723
1991 Increased activity of the eEF-2 specific, Ca2+ and calmodulin dependent protein kinase III during the S-phase in Ehrlich ascites cells. Biochemical and biophysical research communications 19 1659415
2023 Toosendanin targeting eEF2 impedes Topoisomerase I & II protein translation to suppress esophageal squamous cell carcinoma growth. Journal of experimental & clinical cancer research : CR 18 37088855
2022 Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer's disease model mice. Journal of neurochemistry 18 34932218
2022 eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior. EMBO reports 18 35993189
2008 Lopinavir impairs protein synthesis and induces eEF2 phosphorylation via the activation of AMP-activated protein kinase. Journal of cellular biochemistry 18 18712774
1989 Identification of Nsp100 as elongation factor 2 (EF-2). FEBS letters 18 2759242
2022 Inhibition of LDHA to induce eEF2 release enhances thrombocytopoiesis. Blood 17 35176139
2018 Tight interaction of eEF2 in the presence of Stm1 on ribosome. Journal of biochemistry 17 29069440
2013 Differential regulation of eEF2 and p70S6K by AMPKalpha2 in heart. Biochimica et biophysica acta 17 23466593
2020 Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae. Toxins 16 33374361

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