{"gene":"EEF1A1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2000,"finding":"Crystal structure of the eEF1A–eEF1Bα complex determined at 1.67 Å resolution revealed that eEF1Bα inserts one end between the switch 1 and 2 regions of eEF1A to destroy the Mg²⁺ binding site, and the other end contacts domain 2 of eEF1A in the region that binds the CCA-aminoacyl end of tRNA, suggesting competition between eEF1Bα and aa-tRNA as a central element in channeling translation substrates.","method":"X-ray crystallography (1.67 Å), structural analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution crystal structure with mechanistic interpretation, independently followed up by additional crystal structures from the same group","pmids":["11106763"],"is_preprint":false},{"year":2001,"finding":"Crystal structures of eEF1A–eEF1Bα–GDP–Mg²⁺, –GDP, and –GDPNP intermediates defined the nucleotide exchange mechanism; a lethal K205A mutation in eEF1Bα that inserts into the Mg²⁺ binding site of eEF1A confirmed the essential role of Mg²⁺ displacement in nucleotide exchange.","method":"X-ray crystallography (2.05–3.0 Å), site-directed mutagenesis, in vivo viability assay","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures plus functional mutagenesis validating mechanism","pmids":["11373622"],"is_preprint":false},{"year":1998,"finding":"Site-directed mutagenesis of yeast eEF1A at the nucleotide specificity sequence NKMD (residues 153–156) produced viable mutants with increased Km for GTP and reduced GTP hydrolysis rates; N153D was lethal, establishing that this sequence is critical for GTPase function and translational fidelity.","method":"Site-directed mutagenesis, in vitro poly(U)-directed translation assay, GTP hydrolysis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro translation with purified mutant proteins and mutagenesis, single lab","pmids":["9786872"],"is_preprint":false},{"year":2002,"finding":"Exportin 5 (Exp5/RanBP21) mediates nuclear export of eEF1A indirectly via aminoacylated tRNAs; eEF1A binds Exp5 only through aa-tRNA, not directly. Fractionation showed that eEF1A and all other elongation factors are strictly excluded from nuclei, arguing that nuclear translation is actively suppressed.","method":"Nuclear fractionation, transport reconstitution assays, subcellular localization","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical fractionation and transport reconstitution, multiple translation factors examined, consistent with known biology","pmids":["12426392"],"is_preprint":false},{"year":2003,"finding":"TCTP (translationally controlled tumor protein) acts as a guanine nucleotide dissociation inhibitor (GDI) for eEF1A: it preferentially stabilizes the GDP-bound form of eEF1A and impairs the GDP→GTP exchange promoted by eEF1Bβ, as shown by in vitro and in vivo binding assays.","method":"Yeast two-hybrid, co-immunoprecipitation, MS, in vitro nucleotide exchange assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro nucleotide exchange biochemistry plus multiple binding confirmation methods (Y2H, Co-IP, MS)","pmids":["14623968"],"is_preprint":false},{"year":2004,"finding":"eEF1A·GTP binding to the valylated 3′ tRNA-like structure of TYMV genomic RNA strongly represses minus-strand RNA synthesis by the viral RdRp in vitro; repression was aa-tRNA-dependent and required eEF1A·GTP but not the GDP form, suggesting a regulatory switch between translation and replication roles.","method":"In vitro RdRp transcription assay, eEF1A·GTP binding competition","journal":"Virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro RdRp assay with purified components and dose-response, single lab","pmids":["15033564"],"is_preprint":false},{"year":2007,"finding":"eEF1A binds the 3′ stem-loop of West Nile virus genomic RNA and colocalizes with viral replication complexes; mutations that decreased in vitro eEF1A binding to the 3′ SL reduced viral minus-strand RNA synthesis without affecting polyprotein translation, establishing that eEF1A facilitates flavivirus minus-strand synthesis.","method":"RNase footprinting, nitrocellulose filter binding, infectious clone mutagenesis, minus-strand RNA quantification, co-immunoprecipitation, immunofluorescence colocalization","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (footprinting, mutagenesis in infectious clone, CoIP, imaging) in single study","pmids":["17626087"],"is_preprint":false},{"year":2008,"finding":"eEF1A plays a central role in nuclear export of proteins in mammalian cells via a transcription-dependent nuclear export motif (TD-NEM); eEF1A interacts specifically with TD-NEM of VHL and PABP1, and siRNA knockdown or antibody depletion of eEF1A prevents nuclear export of TD-NEM-containing proteins. eEF1A acts from the cytoplasmic face of the nuclear envelope without itself entering the nucleus.","method":"siRNA knockdown, antibody-mediated depletion, in vivo and in vitro nuclear export assay, point mutagenesis of TD-NEM, actinomycin D treatment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (siRNA KD, antibody depletion, in vitro export, mutagenesis) in single lab","pmids":["18799616"],"is_preprint":false},{"year":2008,"finding":"The SAM domain of RhoGAP DLC1 binds eEF1A1 (EF1A1); structural and mutagenesis analysis identified F38/L39 in the DLC1 SAM hydrophobic patch as an indispensable interaction motif. DLC1 SAM facilitates redistribution of eEF1A1 to the membrane periphery upon growth factor stimulation, and this interaction is required for full DLC1-mediated suppression of cell migration.","method":"Protein precipitation/MS, NMR solution structure of DLC1-SAM, site-directed mutagenesis, co-immunoprecipitation, cell migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — NMR structure, mutagenesis, binding confirmation, functional migration assay; multiple methods in one study","pmids":["19158340"],"is_preprint":false},{"year":2008,"finding":"BPOZ-2 directly binds eEF1A1 through its ankyrin repeats and both BTB/POZ domains (interacting with domains I and III of eEF1A1), promotes eEF1A1 ubiquitylation and degradation, inhibits GTP binding to eEF1A1, and suppresses translation in an in vitro reticulocyte assay.","method":"Yeast two-hybrid, pull-down, co-immunoprecipitation, in vitro ubiquitylation assay, GTP-binding assay, in vitro translation assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro biochemical assays and co-IP, single lab","pmids":["18459963"],"is_preprint":false},{"year":2009,"finding":"The Legionella pneumophila Dot/Icm effector SidI specifically interacts with eEF1A and eEF1Bγ, inhibiting host protein synthesis; SidI mutants retaining target-binding but lacking toxicity were isolated, and L. pneumophila infection induces eEF1A-mediated HSF1 activation in a virulence-dependent manner.","method":"Yeast toxicity assay, co-immunoprecipitation, protein synthesis inhibition assay, SidI substitution mutagenesis, HSF1 activation measurement","journal":"Cellular microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by co-IP, functional mutagenesis separates binding from toxicity; single lab","pmids":["19386084"],"is_preprint":false},{"year":2009,"finding":"EF1A1 binds the 5′-UTR of osteopontin (OPN) mRNA to regulate OPN mRNA stability; this interaction is actin-dependent: EF1A1 bound to F-actin in Hep3B cells is unavailable for mRNA binding, and pharmacologic increase of the G:F actin ratio releases EF1A1 to bind OPN mRNA and increase its half-life.","method":"mRNA half-life assay, RNA binding assay, actin co-sedimentation, pharmacologic G:F actin manipulation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (half-life, binding, actin manipulation) in one lab","pmids":["19026636"],"is_preprint":false},{"year":2010,"finding":"TGF-β type I receptor (TβR-I) phosphorylates eEF1A1 at Ser300 in vitro and in vivo; phosphorylation at Ser300 reduces aa-tRNA binding to eEF1A1 and inhibits protein synthesis and cell proliferation. Phosphomimetic Ser300 mutations phenocopy TGF-β-dependent inhibition of translation.","method":"In vitro kinase assay, site-directed mutagenesis, in vivo phosphorylation analysis, in vitro translation assay, cell proliferation assay","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution plus in vivo phosphorylation plus functional translation/proliferation readouts, multiple orthogonal methods, single lab","pmids":["20832312"],"is_preprint":false},{"year":2010,"finding":"eEF1Bα disrupts eEF1A-induced actin organization, and eEF1Bα F163 in the domain shared with actin and aa-tRNA binding governs this activity. Combining the F163A lethal mutation with W130A intragenic suppressor or with the K205A mutation dramatically reduces eEF1Bα–eEF1A affinity and restores viability while increasing actin bundling, establishing that eEF1Bα coordinates the dual roles of eEF1A in actin organization and translation.","method":"Site-directed mutagenesis, actin bundling assay, nucleotide exchange activity assay, yeast growth phenotype, cell morphology analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus in vitro biochemistry, single lab","pmids":["19095653"],"is_preprint":false},{"year":2010,"finding":"eEF1A·GDP (but not eEF1A·GTP) directly activates sphingosine kinase 1 (SK1) in vitro; enhancing cellular eEF1A·GDP levels via TCTP (a GDI) increases SK1 activity in cells. The truncated oncogenic isoform PTI-1, which lacks the G-protein domain, constitutively activates SK1, and SK1 inhibition blocks PTI-1-induced neoplastic transformation.","method":"In vitro SK1 activity assay with GTP/GDP-loaded eEF1A, cell-based SK1 activity assay, dominant-negative SK1 and chemical inhibitor rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro activity reconstitution plus cell-based epistasis, single lab","pmids":["20838377"],"is_preprint":false},{"year":2011,"finding":"eEF1A binds the C-terminal domain (CTD) of Gcn2 kinase independently of ribosomes; this interaction is reduced during amino acid starvation and by uncharged tRNAs in vitro. Purified eEF1A inhibits Gcn2-mediated phosphorylation of eIF2α but not Gcn2 autophosphorylation, identifying eEF1A as a Gcn2 inhibitor that modulates the amino acid starvation response.","method":"Affinity purification (His-eEF1A), co-immunoprecipitation, GST pulldown with purified proteins, in vitro Gcn2 kinase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — purified protein in vitro kinase assay plus co-IP and pulldown; multiple orthogonal methods in one study","pmids":["21849502"],"is_preprint":false},{"year":2011,"finding":"Cytoplasmic AID in B cells exists in stoichiometric complex with eEF1A; the interaction depends on the C-terminal domain of eEF1A (not the GTP or tRNA binding regions) and on the AID region responsible for cytosolic retention, establishing eEF1A as a cytosolic retention factor for AID.","method":"Endogenous tagging of AID, co-immunoprecipitation, domain mapping, sucrose gradient sedimentation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — endogenously tagged protein (avoiding overexpression artefacts), reciprocal IP, domain mapping; multiple methods, single lab","pmids":["22042842"],"is_preprint":false},{"year":2012,"finding":"PUF proteins (FBF) and Argonaute (CSR-1/Ago) form a conserved complex with eEF1A in both C. elegans and mammals; FBF-1–CSR-1 heterodimer inhibits eEF1A GTPase activity in vitro; the mammalian PUM2–Ago–eEF1A complex inhibits translation of reporters after initiation, causing ribosome accumulation within the ORF at the site where the nascent peptide exits the ribosome.","method":"Co-immunoprecipitation, recombinant protein pulldown, in vitro GTPase assay, in vitro translation with polysome/ribosome profiling","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro GTPase assay, in vitro translation, co-IP; replicated in two organisms with multiple methods","pmids":["22231398"],"is_preprint":false},{"year":2012,"finding":"eEF1A associates with defective ribosomal products (DRiPs) at the ribosome to generate a signal that triggers aggresome formation upon proteasome inhibition; the Legionella toxin SidI, which inhibits translation but spares this eEF1A function, demonstrated that the aggresome-signaling role of eEF1A is separable from its translation elongation function.","method":"siRNA knockdown, aggresome formation assay, SidI toxin pharmacological dissection","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype plus pharmacological tool to separate functions; single lab","pmids":["22357952"],"is_preprint":false},{"year":2013,"finding":"eEF1A binds to Snail transcription factors (via their SNAG domain) when Snail is bound to the E-cadherin promoter, and escorts Snail from the nucleus to the cytoplasm via the Exportin5–aa-tRNA complex; this export is regulated by phosphorylation of Snail, establishing a nuclear role for eEF1A in attenuating transcription factor activity.","method":"Co-immunoprecipitation, nuclear export assay, chromatin immunoprecipitation, phosphorylation analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, nuclear export functional assay, ChIP; multiple methods; single lab","pmids":["24209753"],"is_preprint":false},{"year":2014,"finding":"eEF1A1 isoform (but not eEF1A2) participates in the entire heat shock response: upon stress it recruits HSF1 to the HSP70 promoter to activate transcription, then associates with elongating RNA Pol II and the HSP70 mRNA 3′UTR to stabilize it and facilitate nuclear-to-ribosome transport. eEF1A1 depletion severely impairs HSR and thermotolerance.","method":"siRNA knockdown, ChIP, RNA immunoprecipitation, live-cell imaging, RT-qPCR, thermotolerance assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, RIP, imaging, KD with defined phenotypes) in single rigorous study","pmids":["25233275"],"is_preprint":false},{"year":2014,"finding":"METTL10 trimethylates eEF1A1 at lysine 318 in mammalian cells; siRNA-mediated knockdown of METTL10 decreases eEF1A1 K318 methylation in vivo, as confirmed using a selenium-based SAM analog (ProSeAM) and quantitative MS.","method":"ProSeAM chemical probe, affinity purification, quantitative MS, siRNA knockdown, biochemical characterization","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — chemical probe plus MS identification plus siRNA loss-of-function confirmation; multiple methods, single lab","pmids":["25144183"],"is_preprint":false},{"year":2015,"finding":"eEF1A is the cytoplasmic retention factor for AID; the mechanism is independent of protein synthesis but requires a tRNA-free form of eEF1A. eEF1A and HSP90 interactions with AID are inversely correlated and define two sequential complexes: HSP90 produces functional AID, which is then stored by eEF1A in the cytoplasm. Inhibiting eEF1A allows AID nuclear accumulation, increasing class switch recombination and chromosomal translocations.","method":"Chemical inhibition of eEF1A, co-immunoprecipitation, nuclear export assay, class switch recombination assay, chromosomal translocation assay","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple functional outputs (CSR, translocation), pharmacological and biochemical dissection of two distinct AID complexes; single lab but comprehensive","pmids":["25824822"],"is_preprint":false},{"year":2015,"finding":"Direct interaction between eEF1A and HIV-1 reverse transcriptase (RT) has KD ~3–4 nM; both RT thumb and connection domains are required. A single W252A mutation in the RT thumb impairs co-IP with eEF1A and reduces late reverse transcription and virus replication. Didemnin B binds eEF1A and inhibits HIV-1 reverse transcription by >2 logs; W252A RT confers resistance to didemnin B, confirming eEF1A–RT interaction as the antiviral target.","method":"Biolayer interferometry, co-immunoprecipitation, site-directed mutagenesis, reverse transcription quantification, virus replication assay, drug resistance analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative binding assay plus mutagenesis plus drug resistance validation; multiple orthogonal methods","pmids":["26624286"],"is_preprint":false},{"year":2016,"finding":"FAT10 competes with ubiquitin for binding to the same lysines on eEF1A1, forming FAT10–eEF1A1 complexes instead of Ub–eEF1A1 complexes; FAT10 overexpression therefore decreases eEF1A1 ubiquitination and proteasomal degradation, stabilizing eEF1A1 and promoting cancer cell proliferation.","method":"Co-immunoprecipitation, ubiquitination assay, lysine mutagenesis, cell proliferation assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination competition assay, mutagenesis; single lab","pmids":["27312528"],"is_preprint":false},{"year":2017,"finding":"METTL21B specifically trimethylates eEF1A Lys-165 in an aminoacyl-tRNA- and GTP-dependent manner; this methylation is dynamic and inducible by ER stress. Genetic ablation of METTL21B in mammalian cells alters mRNA translation dynamics and changes codon-specific translation rates as measured by ribosome profiling. METTL21B also accumulates in centrosomes.","method":"In vitro methylation assay, in vivo methylation analysis, METTL21B knockout, ribosome profiling, immunofluorescence localization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro enzyme assay, genetic KO with ribosome profiling, GTP/aa-tRNA dependence established; multiple orthogonal methods","pmids":["28108655"],"is_preprint":false},{"year":2017,"finding":"A novel 7β-strand KMT (eEF1A-KMT4 / EEF1AKMT4) trimethylates eEF1A at Lys36 in vitro and in vivo; KO of this enzyme in mammalian cells alters translation dynamics and changes translation speed of distinct codons by ribosome profiling.","method":"In vitro methylation assay, KO cell lines, ribosome profiling, active site mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme reconstitution, genetic KO, ribosome profiling; multiple methods, single lab","pmids":["28520920"],"is_preprint":false},{"year":2017,"finding":"Expanded polyalanine tracts function as nuclear export signals by interacting with eEF1A1; GST-pulldown and MS identified eEF1A1 as the binding partner. Knockdown of eEF1A1 partially corrects cytoplasmic mislocalization of expanded poly(A) proteins and restores their nuclear transcription factor function.","method":"GST pulldown/MS, siRNA knockdown, subcellular localization assay, transcriptional reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown/MS plus siRNA loss-of-function with localization and functional readout; single lab","pmids":["28246169"],"is_preprint":false},{"year":2018,"finding":"Human METTL13 contains two distinct methyltransferase domains: one methylates the eEF1A N-terminus and the other dimethylates Lys55. Structural analysis provided mechanistic detail on N-terminal recognition. Loss of METTL13 function alters translation dynamics and codon-specific translation rates by ribosome profiling.","method":"In vitro methylation biochemistry, X-ray crystallography (structural analysis), ribosome profiling, domain mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro biochemistry plus ribosome profiling; multiple orthogonal methods in single study","pmids":["30143613"],"is_preprint":false},{"year":2019,"finding":"METTL13 dimethylates eEF1A Lys55 (eEF1AK55me2) and this modification increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 deletion and loss of eEF1AK55me2 dramatically reduce Ras-driven neoplastic growth in mouse models and patient-derived xenografts.","method":"In vitro GTPase assay with methylated vs unmethylated eEF1A, METTL13 KO mouse models, PDX models, metabolic labeling of protein synthesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro GTPase reconstitution plus in vivo mouse and PDX models; multiple orthogonal methods; high-impact journal with rigorous controls","pmids":["30612740"],"is_preprint":false},{"year":2021,"finding":"Plitidepsin's antiviral activity against SARS-CoV-2 is mediated through inhibition of host eEF1A; a drug-resistant eEF1A mutant demonstrated this mechanistic link, and plitidepsin reduced viral replication by two orders of magnitude in mouse models.","method":"Drug-resistant mutant selection, in vitro antiviral assay, in vivo mouse infection models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — drug-resistant mutant mechanistically validates eEF1A as target, replicated in two mouse models","pmids":["33495306"],"is_preprint":false},{"year":2022,"finding":"Single-molecule fluorescence imaging and cryo-EM showed that didemnin B and ternatin-4 both bind to a common site on eEF1A·GTP·aa-tRNA ternary complex and trap eEF1A in an intermediate state of aa-tRNA selection, preventing eEF1A release and aa-tRNA accommodation on the ribosome; the two compounds produce distinct effects on ternary complex dynamics that explain differences in their inhibition efficacy.","method":"Single-molecule FRET imaging, cryogenic electron microscopy, in vitro translation assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures plus single-molecule dynamics; two orthogonal structural/biophysical approaches in one study","pmids":["36264623"],"is_preprint":false},{"year":2022,"finding":"SR-A3 (a ternatin-family cyclic peptide) binds eEF1A with enhanced residence time and rebinding kinetics compared to SS-A3 epimer; single-molecule fluorescence imaging of elongation reactions with purified eEF1A defined the stereospecific binding kinetics. Prolonged target engagement correlated with antitumor efficacy in a Myc-driven mouse lymphoma model.","method":"Single-molecule fluorescence imaging (in vitro reconstituted elongation), stereospecific synthesis, in vivo mouse lymphoma model","journal":"Nature chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — single-molecule biophysics with purified eEF1A plus in vivo validation; multiple methods, single lab","pmids":["36123449"],"is_preprint":false},{"year":2006,"finding":"Tetrahymena eEF1A forms homodimers that bundle F-actin; eEF1A dimers (but not monomers) bind and bundle F-actin at a ~1:1 stoichiometry. Ca²⁺/calmodulin converts eEF1A dimers to monomers, releasing them from actin bundles in a reversible manner, providing a Ca²⁺-dependent regulatory mechanism for actin organization.","method":"Gel filtration chromatography, cosedimentation assay, electron microscopy, Ca²⁺/calmodulin treatment","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro biochemical assays with isolated monomer/dimer fractions; single lab with Tetrahymena ortholog","pmids":["16877446"],"is_preprint":false},{"year":2008,"finding":"Domain 3 of Tetrahymena eEF1A is the primary F-actin binding domain and influences dimer formation; all three domains bind calmodulin in a Ca²⁺-dependent manner with distinct Ca²⁺ concentration thresholds, with domain 3 serving a pivotal role in Ca²⁺/calmodulin-regulated actin bundling.","method":"GST-domain fusion protein binding assays, cosedimentation, calmodulin interaction assay with Ca²⁺ titration","journal":"Zoological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion biochemistry with recombinant proteins; single lab, Tetrahymena ortholog","pmids":["18275242"],"is_preprint":false},{"year":2007,"finding":"ZPR1 binds preferentially to GDP-bound eEF1A; crystal structure of the ZPR1 domain tandem was determined and structure-based mutational analysis identified a conserved eEF1A-binding epitope required for normal cell growth, proliferation, and cell cycle progression. ZPR1 efficiently displaces eEF1Bα from nucleotide-free eEF1A complexes, suggesting it functions as a negative regulator of eEF1A activation.","method":"X-ray crystallography, co-immunoprecipitation, nucleotide exchange displacement assay, site-directed mutagenesis, yeast complementation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure, biochemical displacement assay, mutagenesis with functional complementation; multiple methods in one study","pmids":["17704259"],"is_preprint":false},{"year":2007,"finding":"PASKIN kinase interacts with eEF1A1 through its PAS A and kinase domains (binding eEF1A1 C-terminus) and phosphorylates eEF1A1 primarily at Thr432; wild-type but not kinase-inactive PASKIN increases in vitro translation of a reporter cRNA, suggesting that PASKIN-dependent phosphorylation of eEF1A1 promotes translation.","method":"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, in vitro kinase assay, MS, site-directed mutagenesis, in vitro translation assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay with MS identification of phosphosite plus translation readout; single lab","pmids":["17595531"],"is_preprint":false},{"year":2010,"finding":"eEF1A1 (but not eEF1A2) interacts with Ca²⁺/calmodulin; this interaction is predicted by molecular dynamics showing a less flexible calmodulin-binding region in eEF1A1, and confirmed experimentally by ELISA-based binding test. Calmodulin binding interferes with tRNA-binding and actin-bundling activities of eEF1A1 in vitro.","method":"Multiple molecular dynamics simulation, ELISA-based calmodulin binding assay, in vitro tRNA binding, in vitro actin bundling assay","journal":"BMC structural biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MD simulation plus experimental ELISA binding plus in vitro functional assays; single lab","pmids":["18221514"],"is_preprint":false},{"year":2010,"finding":"PKCβI co-immunoprecipitates with eEF1A in the nucleus of insulin-stimulated C2C12 myoblasts and phosphorylates eEF1A2 at Ser53 in vitro; the association between eEF1A2 and PKCβI is dependent on the phosphorylation status of eEF1A2, establishing PKCβI as a nuclear kinase for this elongation factor.","method":"Nuclear fractionation, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, LC-MS/MS proteomics","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus nuclear co-IP plus site mutagenesis; note this abstract focuses on eEF1A2 Ser53 but the nuclear fractionation context includes eEF1A1 identification; single lab","pmids":["20923971"],"is_preprint":false},{"year":2002,"finding":"Mammalian eEF1A·GDP forms a stable ternary complex with uncharged tRNA (Kd ~20 nM) and a quaternary complex with phenylalanyl-tRNA synthetase (Kd ~9 nM); direct eEF1A–PheRS interaction (Kd ~21 nM) is accelerated by tRNA, supporting a tRNA-channeling model in which the GDP-bound form of eEF1A participates in tRNA delivery to aminoacyl-tRNA synthetase.","method":"Gel retardation assay, surface plasmon resonance (BIAcore), fluorescence binding assay","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — quantitative binding assays with purified components; single lab","pmids":["12354112"],"is_preprint":false},{"year":2024,"finding":"Chp1 is a dedicated ribosome-associated chaperone for eEF1A biogenesis: it is recruited to the ribosome via the nascent polypeptide-associated complex (NAC) during eEF1A synthesis. Absence of Chp1 causes instant proteolysis of nascent eEF1A, widespread protein aggregation, Hsf1 stress activation, and reduced cellular fitness. Chp1 also protects pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy from degradation.","method":"Ribosome association assay, proteomics, protein aggregation assay, Hsf1 reporter assay, fitness assay, pathogenic variant expression","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple functional readouts (proteolysis, aggregation, stress response, fitness) with genetic deletion; single lab but comprehensive mechanistic characterization","pmids":["38360885"],"is_preprint":false},{"year":2019,"finding":"Archaeal stalk protein aP1 C-terminal domain (CTD) binds eEF1A·GTP in a space between domains 1 and 3 of eEF1A (crystal structure at 3.0 Å); comparison with the aP1-CTD·eEF1A·GDP structure shows a marked change in binding mode upon GTP/GDP conformational switch, revealing how the stalk supports efficient elongation by engaging eEF1A in both nucleotide states.","method":"X-ray crystallography (3.0 Å), biochemical binding assay, in vitro translation assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation; archaeal ortholog; single lab","pmids":["31611569"],"is_preprint":false},{"year":2008,"finding":"eEF1A associates with defective ribosomal products via its translation elongation activity and triggers aggresome formation; the novel eEF1A binding protein IGFN1 (found in yeast two-hybrid screen of human skeletal muscle library) interacts with eEF1A in vitro and is upregulated upon muscle denervation, suggesting it downregulates protein synthesis via eEF1A during denervation.","method":"Yeast two-hybrid, in vitro protein interaction confirmation","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid plus in vitro confirmation; functional link proposed but not directly demonstrated","pmids":["18756455"],"is_preprint":false},{"year":2012,"finding":"eEF1A1 interacts with eEF1A1 is a cytoplasmic retention factor for AID; the mechanism requires a tRNA-free form of eEF1A confirmed by the functional consequence that inhibiting eEF1A releases AID to the nucleus increasing class switch recombination. (Note: primary mechanistic finding captured under PMID 22042842 and 25824822 above.)","method":"Chemical inhibition, nuclear accumulation assay","journal":"The Journal of experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — this entry is redundant with 25824822; included here only for completeness; see 25824822 for full detail","pmids":["25824822"],"is_preprint":false}],"current_model":"eEF1A1 is a multifunctional GTPase that in its canonical role delivers aminoacyl-tRNA to the ribosomal A-site (GTP-bound form) and undergoes nucleotide exchange by eEF1Bα (which displaces Mg²⁺ via its switch-region insertion, a mechanism visualized by crystal structures); beyond translation, the GDP-bound form activates sphingosine kinase 1, the protein is phosphorylated by TβR-I at Ser300 to suppress translation and by PASKIN at Thr432, and is extensively trimethylated at multiple lysines (K36 by eEF1A-KMT4, K55 by METTL13 which increases GTPase activity and translational output, K165 by METTL21B in a GTP/aa-tRNA-dependent and inducible manner, K318 by METTL10), with these methylations modulating codon-specific translation rates; eEF1A1 bundles F-actin through dimer formation regulated by Ca²⁺/calmodulin; it acts as a cytosolic retention factor for AID (requiring a tRNA-free form), participates in nuclear export of SNAG transcription factors and TD-NEM-containing proteins via the Exportin5–aa-tRNA pathway, coordinates the heat shock response by recruiting HSF1 to the HSP70 promoter and stabilizing HSP70 mRNA for ribosomal delivery, regulates mRNA stability (e.g., OPN 5′UTR) in an actin-state-dependent manner, inhibits the Gcn2 stress kinase, and interacts directly with HIV-1 RT to support reverse transcription—all while requiring the dedicated ribosome-associated chaperone Chp1 for its own proper co-translational folding."},"narrative":{"mechanistic_narrative":"eEF1A1 is a multifunctional GTPase whose canonical role is the GTP-dependent delivery of aminoacyl-tRNA to the elongating ribosome, a function defined biochemically through its nucleotide-specificity NKMD motif required for GTP hydrolysis and translational fidelity [PMID:9786872] and structurally through crystal structures of the eEF1A–eEF1Bα complex showing that the exchange factor inserts between the switch regions to destroy the Mg²⁺-binding site and competes with the CCA-aminoacyl end of tRNA, channeling translation substrates [PMID:11106763, PMID:11373622]. Cyclic-peptide inhibitors (didemnin B, ternatin-4, SR-A3) trap eEF1A·GTP·aa-tRNA ternary complexes in an intermediate state of aa-tRNA selection, defining the drug-binding site and the dynamics of factor release [PMID:36264623, PMID:36123449]. eEF1A activity is gated by a network of regulators and modifications: TCTP and ZPR1 act as nucleotide-dissociation inhibitors that favor the GDP-bound form [PMID:14623968, PMID:17704259], TGF-β receptor TβR-I phosphorylates Ser300 to reduce aa-tRNA binding and suppress translation [PMID:20832312], and a suite of lysine methyltransferases—eEF1A-KMT4 (K36), METTL13 (N-terminus and K55), METTL21B (K165), and METTL10 (K318)—trimethylate the factor to tune codon-specific elongation rates, with METTL13-mediated K55 dimethylation increasing intrinsic GTPase activity and supporting Ras-driven oncogenic growth [PMID:28520920, PMID:30143613, PMID:30612740, PMID:28108655, PMID:25144183]. Beyond elongation, eEF1A1 carries diverse moonlighting functions: it bundles F-actin through Ca²⁺/calmodulin-regulated dimerization [PMID:16877446, PMID:18275242, PMID:18221514], orchestrates the heat shock response by recruiting HSF1 to the HSP70 promoter and stabilizing HSP70 mRNA [PMID:25233275], exports SNAG-domain transcription factors and TD-NEM/polyalanine-containing proteins from the nucleus via the Exportin5–aa-tRNA pathway [PMID:18799616, PMID:24209753, PMID:28246169], retains AID in the cytoplasm in a tRNA-free state to limit class switch recombination [PMID:22042842, PMID:25824822], inhibits the Gcn2 stress kinase [PMID:21849502], and in its GDP-bound form activates sphingosine kinase 1 [PMID:20838377]. eEF1A is co-opted by pathogens, supporting viral RNA replication and HIV-1 reverse transcription [PMID:15033564, PMID:17626087, PMID:26624286] and serving as the host target of antiviral plitidepsin against SARS-CoV-2 [PMID:33495306]. Its own biogenesis requires the dedicated ribosome-associated chaperone Chp1, recruited via NAC, which protects nascent eEF1A from proteolysis [PMID:38360885].","teleology":[{"year":1998,"claim":"Established that a defined nucleotide-specificity motif governs eEF1A's GTPase chemistry and translational fidelity, anchoring its catalytic identity.","evidence":"Site-directed mutagenesis of yeast eEF1A NKMD motif with in vitro poly(U) translation and GTP hydrolysis assays","pmids":["9786872"],"confidence":"High","gaps":["Does not resolve the full conformational cycle on the ribosome","Yeast ortholog; human residue effects inferred"]},{"year":2001,"claim":"Resolved the atomic mechanism of guanine-nucleotide exchange, showing eEF1Bα drives GDP release by displacing the catalytic Mg²⁺ and competing with aa-tRNA binding.","evidence":"Crystal structures of eEF1A–eEF1Bα at 1.67Å and of GDP/GDPNP intermediates plus lethal K205A mutagenesis","pmids":["11106763","11373622"],"confidence":"High","gaps":["Static structures do not capture exchange kinetics in cells","Does not address regulation of exchange by upstream signals"]},{"year":2007,"claim":"Identified ZPR1 (and earlier TCTP) as nucleotide-state-selective regulators that displace the exchange factor and bias eEF1A toward the GDP-bound form, revealing layered control of activation.","evidence":"Crystallography, co-IP, nucleotide-exchange displacement assays and yeast complementation; TCTP via Y2H/Co-IP/exchange assay","pmids":["17704259","14623968"],"confidence":"High","gaps":["Physiological conditions selecting between these regulators unresolved","Connection to specific signaling inputs not mapped"]},{"year":2010,"claim":"Showed that signaling kinases directly modulate eEF1A translational output, with TβR-I phosphorylation of Ser300 suppressing translation and PASKIN phosphorylation of Thr432 promoting it.","evidence":"In vitro kinase assays, phosphosite mutagenesis, in vitro translation and proliferation readouts","pmids":["20832312","17595531"],"confidence":"High","gaps":["Crosstalk between phosphosites not characterized","Phosphatases reversing these marks unknown"]},{"year":2017,"claim":"Defined a dedicated lysine-methyltransferase network (eEF1A-KMT4/K36, METTL21B/K165, METTL10/K318) that post-translationally tunes codon-specific elongation rates.","evidence":"In vitro methylation assays, enzyme knockouts with ribosome profiling, chemical-probe MS","pmids":["28520920","28108655","25144183"],"confidence":"High","gaps":["How individual marks integrate to set codon usage is unresolved","Demethylation/turnover of these marks not addressed"]},{"year":2019,"claim":"Demonstrated that METTL13 methylation of the N-terminus and K55 boosts intrinsic GTPase activity and translational output, linking eEF1A modification to Ras-driven oncogenesis.","evidence":"In vitro GTPase assays with methylated eEF1A, crystallography, METTL13 KO mouse and PDX models","pmids":["30143613","30612740"],"confidence":"High","gaps":["Selectivity of dependence across tumor genotypes not fully defined","Mechanism linking GTPase rate to growth not dissected at single-codon level"]},{"year":2006,"claim":"Established eEF1A's actin-bundling moonlighting activity as a Ca²⁺/calmodulin-regulated, dimer-dependent process distinct from translation.","evidence":"Gel filtration, cosedimentation, EM and Ca²⁺/calmodulin treatment in Tetrahymena; domain mapping; ELISA calmodulin binding","pmids":["16877446","18275242","18221514"],"confidence":"Medium","gaps":["Largely ortholog-based; human in vivo relevance partly inferred","Coordination with translational pool in cells not quantified"]},{"year":2014,"claim":"Revealed eEF1A1 as a master coordinator of the heat shock response acting at both transcription (HSF1 recruitment) and mRNA stability levels, an isoform-specific nuclear-associated function.","evidence":"siRNA knockdown, ChIP, RIP, live-cell imaging and thermotolerance assays","pmids":["25233275"],"confidence":"High","gaps":["Mechanism of HSF1 recruitment by a cytoplasmic factor not structurally defined","Single-lab study"]},{"year":2015,"claim":"Defined eEF1A as a cytoplasmic retention factor and nuclear-export adaptor controlling localization of regulatory proteins, requiring a tRNA-free form for AID retention and the Exportin5–aa-tRNA route for transcription-factor export.","evidence":"Endogenous tagging, co-IP, domain mapping, chemical inhibition with CSR/translocation readouts; export assays for SNAG and TD-NEM/polyalanine proteins","pmids":["25824822","22042842","18799616","24209753","28246169"],"confidence":"High","gaps":["How the same factor distinguishes retention versus export substrates is unresolved","Structural basis of substrate recognition not determined"]},{"year":2021,"claim":"Validated eEF1A as the host target of antiviral cyclic peptides and clarified the inhibitory mechanism as trapping of the ternary complex during aa-tRNA selection.","evidence":"Drug-resistant mutant selection, cryo-EM and single-molecule FRET, in vivo SARS-CoV-2 and lymphoma models; HIV-1 RT binding via biolayer interferometry","pmids":["33495306","36264623","36123449","26624286"],"confidence":"High","gaps":["Therapeutic window between antiviral/antitumor effect and translation toxicity not defined","Selectivity over eEF1A2 not fully addressed"]},{"year":2024,"claim":"Identified Chp1 as a dedicated ribosome-associated chaperone required for eEF1A biogenesis, showing nascent eEF1A needs specialized co-translational protection from degradation.","evidence":"Ribosome association, proteomics, aggregation and Hsf1 reporter assays, pathogenic variant expression","pmids":["38360885"],"confidence":"High","gaps":["Structural basis of Chp1–nascent eEF1A recognition unknown","Human disease relevance shown for eEF1A2 variants, not eEF1A1"]},{"year":null,"claim":"How eEF1A's many moonlighting roles (actin, nuclear export, stress signaling, viral support) are partitioned from the translational pool within a single cell, and how nucleotide state, modification, and partner availability jointly select among them, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking PTM state to functional partitioning","Quantitative flux between translational and non-translational pools unmeasured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[2,0,1,29]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[5,6,11,39]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[33,34,37]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,19,16]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[2,12,17]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,16,22]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[33,11]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[17,31,40]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,20]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2,29]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[20,15]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[7,19,16]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,30,29]}],"complexes":["eEF1A–eEF1Bα (eEF1B complex)","eEF1A·GTP·aa-tRNA ternary complex","PUM2–Ago–eEF1A complex"],"partners":["EEF1B2","TPT1","ZPR1","METTL13","AICDA","EIF2AK4","SNAI1","VHL"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P68104","full_name":"Elongation factor 1-alpha 1","aliases":["Elongation factor Tu","EF-Tu","Eukaryotic elongation factor 1 A-1","eEF1A-1","Leukocyte receptor cluster member 7"],"length_aa":462,"mass_kda":50.1,"function":"Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis (PubMed:26593721, PubMed:26651998, PubMed:36123449, PubMed:36264623, PubMed:36638793). Base pairing between the mRNA codon and the aa-tRNA anticodon promotes GTP hydrolysis, releasing the aa-tRNA from EEF1A1 and allowing its accommodation into the ribosome (PubMed:26593721, PubMed:26651998, PubMed:36123449, PubMed:36264623, PubMed:36638793). The growing protein chain is subsequently transferred from the P-site peptidyl tRNA to the A-site aa-tRNA, extending it by one amino acid through ribosome-catalyzed peptide bond formation (PubMed:26593721, PubMed:26651998, PubMed:36123449, PubMed:36264623). Also plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with TXK and PARP1 (PubMed:17177976). Also plays a role in cytoskeleton organization by promoting actin bundling (By similarity) (Microbial infection) Required for the translation of viral proteins and viral replication during human coronavirus SARS-CoV-2 infection","subcellular_location":"Cytoplasm; Nucleus; Nucleus, nucleolus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/P68104/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EEF1A1","classification":"Common Essential","n_dependent_lines":378,"n_total_lines":383,"dependency_fraction":0.9869451697127938},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EEF1A1","total_profiled":1310},"omim":[{"mim_id":"620917","title":"SPERMATOGENIC FAILURE 95; SPGF95","url":"https://www.omim.org/entry/620917"},{"mim_id":"617794","title":"EEF1A LYSINE METHYLTRANSFERASE 2; EEF1AKMT2","url":"https://www.omim.org/entry/617794"},{"mim_id":"617793","title":"EEF1A LYSINE METHYLTRANSFERASE 1; EEF1AKMT1","url":"https://www.omim.org/entry/617793"},{"mim_id":"617309","title":"IMMUNOGLOBULIN-LIKE AND FIBRONECTIN TYPE III DOMAINS-CONTAINING PROTEIN 1; IGFN1","url":"https://www.omim.org/entry/617309"},{"mim_id":"616686","title":"SYNAPTOTAGMIN-BINDING CYTOPLASMIC RNA-INTERACTING PROTEIN; SYNCRIP","url":"https://www.omim.org/entry/616686"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EEF1A1"},"hgnc":{"alias_symbol":["EE1A1","EF1A1","EF1alpha1"],"prev_symbol":["EF1A","EEF1A","LENG7"]},"alphafold":{"accession":"P68104","domains":[{"cath_id":"3.40.50.300","chopping":"5-95_102-232","consensus_level":"high","plddt":87.847,"start":5,"end":232},{"cath_id":"2.40.30.10","chopping":"246-332_449-460","consensus_level":"high","plddt":91.1401,"start":246,"end":460},{"cath_id":"2.40.30.10","chopping":"336-442","consensus_level":"high","plddt":91.8903,"start":336,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P68104","model_url":"https://alphafold.ebi.ac.uk/files/AF-P68104-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P68104-F1-predicted_aligned_error_v6.png","plddt_mean":88.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EEF1A1","jax_strain_url":"https://www.jax.org/strain/search?query=EEF1A1"},"sequence":{"accession":"P68104","fasta_url":"https://rest.uniprot.org/uniprotkb/P68104.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P68104/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P68104"}},"corpus_meta":[{"pmid":"33495306","id":"PMC_33495306","title":"Plitidepsin 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channeling translation substrates.\",\n      \"method\": \"X-ray crystallography (1.67 Å), structural analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution crystal structure with mechanistic interpretation, independently followed up by additional crystal structures from the same group\",\n      \"pmids\": [\"11106763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structures of eEF1A–eEF1Bα–GDP–Mg²⁺, –GDP, and –GDPNP intermediates defined the nucleotide exchange mechanism; a lethal K205A mutation in eEF1Bα that inserts into the Mg²⁺ binding site of eEF1A confirmed the essential role of Mg²⁺ displacement in nucleotide exchange.\",\n      \"method\": \"X-ray crystallography (2.05–3.0 Å), site-directed mutagenesis, in vivo viability assay\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures plus functional mutagenesis validating mechanism\",\n      \"pmids\": [\"11373622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Site-directed mutagenesis of yeast eEF1A at the nucleotide specificity sequence NKMD (residues 153–156) produced viable mutants with increased Km for GTP and reduced GTP hydrolysis rates; N153D was lethal, establishing that this sequence is critical for GTPase function and translational fidelity.\",\n      \"method\": \"Site-directed mutagenesis, in vitro poly(U)-directed translation assay, GTP hydrolysis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro translation with purified mutant proteins and mutagenesis, single lab\",\n      \"pmids\": [\"9786872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Exportin 5 (Exp5/RanBP21) mediates nuclear export of eEF1A indirectly via aminoacylated tRNAs; eEF1A binds Exp5 only through aa-tRNA, not directly. Fractionation showed that eEF1A and all other elongation factors are strictly excluded from nuclei, arguing that nuclear translation is actively suppressed.\",\n      \"method\": \"Nuclear fractionation, transport reconstitution assays, subcellular localization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical fractionation and transport reconstitution, multiple translation factors examined, consistent with known biology\",\n      \"pmids\": [\"12426392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TCTP (translationally controlled tumor protein) acts as a guanine nucleotide dissociation inhibitor (GDI) for eEF1A: it preferentially stabilizes the GDP-bound form of eEF1A and impairs the GDP→GTP exchange promoted by eEF1Bβ, as shown by in vitro and in vivo binding assays.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, MS, in vitro nucleotide exchange assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro nucleotide exchange biochemistry plus multiple binding confirmation methods (Y2H, Co-IP, MS)\",\n      \"pmids\": [\"14623968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"eEF1A·GTP binding to the valylated 3′ tRNA-like structure of TYMV genomic RNA strongly represses minus-strand RNA synthesis by the viral RdRp in vitro; repression was aa-tRNA-dependent and required eEF1A·GTP but not the GDP form, suggesting a regulatory switch between translation and replication roles.\",\n      \"method\": \"In vitro RdRp transcription assay, eEF1A·GTP binding competition\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro RdRp assay with purified components and dose-response, single lab\",\n      \"pmids\": [\"15033564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"eEF1A binds the 3′ stem-loop of West Nile virus genomic RNA and colocalizes with viral replication complexes; mutations that decreased in vitro eEF1A binding to the 3′ SL reduced viral minus-strand RNA synthesis without affecting polyprotein translation, establishing that eEF1A facilitates flavivirus minus-strand synthesis.\",\n      \"method\": \"RNase footprinting, nitrocellulose filter binding, infectious clone mutagenesis, minus-strand RNA quantification, co-immunoprecipitation, immunofluorescence colocalization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (footprinting, mutagenesis in infectious clone, CoIP, imaging) in single study\",\n      \"pmids\": [\"17626087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"eEF1A plays a central role in nuclear export of proteins in mammalian cells via a transcription-dependent nuclear export motif (TD-NEM); eEF1A interacts specifically with TD-NEM of VHL and PABP1, and siRNA knockdown or antibody depletion of eEF1A prevents nuclear export of TD-NEM-containing proteins. eEF1A acts from the cytoplasmic face of the nuclear envelope without itself entering the nucleus.\",\n      \"method\": \"siRNA knockdown, antibody-mediated depletion, in vivo and in vitro nuclear export assay, point mutagenesis of TD-NEM, actinomycin D treatment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (siRNA KD, antibody depletion, in vitro export, mutagenesis) in single lab\",\n      \"pmids\": [\"18799616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The SAM domain of RhoGAP DLC1 binds eEF1A1 (EF1A1); structural and mutagenesis analysis identified F38/L39 in the DLC1 SAM hydrophobic patch as an indispensable interaction motif. DLC1 SAM facilitates redistribution of eEF1A1 to the membrane periphery upon growth factor stimulation, and this interaction is required for full DLC1-mediated suppression of cell migration.\",\n      \"method\": \"Protein precipitation/MS, NMR solution structure of DLC1-SAM, site-directed mutagenesis, co-immunoprecipitation, cell migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — NMR structure, mutagenesis, binding confirmation, functional migration assay; multiple methods in one study\",\n      \"pmids\": [\"19158340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BPOZ-2 directly binds eEF1A1 through its ankyrin repeats and both BTB/POZ domains (interacting with domains I and III of eEF1A1), promotes eEF1A1 ubiquitylation and degradation, inhibits GTP binding to eEF1A1, and suppresses translation in an in vitro reticulocyte assay.\",\n      \"method\": \"Yeast two-hybrid, pull-down, co-immunoprecipitation, in vitro ubiquitylation assay, GTP-binding assay, in vitro translation assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro biochemical assays and co-IP, single lab\",\n      \"pmids\": [\"18459963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The Legionella pneumophila Dot/Icm effector SidI specifically interacts with eEF1A and eEF1Bγ, inhibiting host protein synthesis; SidI mutants retaining target-binding but lacking toxicity were isolated, and L. pneumophila infection induces eEF1A-mediated HSF1 activation in a virulence-dependent manner.\",\n      \"method\": \"Yeast toxicity assay, co-immunoprecipitation, protein synthesis inhibition assay, SidI substitution mutagenesis, HSF1 activation measurement\",\n      \"journal\": \"Cellular microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by co-IP, functional mutagenesis separates binding from toxicity; single lab\",\n      \"pmids\": [\"19386084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"EF1A1 binds the 5′-UTR of osteopontin (OPN) mRNA to regulate OPN mRNA stability; this interaction is actin-dependent: EF1A1 bound to F-actin in Hep3B cells is unavailable for mRNA binding, and pharmacologic increase of the G:F actin ratio releases EF1A1 to bind OPN mRNA and increase its half-life.\",\n      \"method\": \"mRNA half-life assay, RNA binding assay, actin co-sedimentation, pharmacologic G:F actin manipulation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (half-life, binding, actin manipulation) in one lab\",\n      \"pmids\": [\"19026636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TGF-β type I receptor (TβR-I) phosphorylates eEF1A1 at Ser300 in vitro and in vivo; phosphorylation at Ser300 reduces aa-tRNA binding to eEF1A1 and inhibits protein synthesis and cell proliferation. Phosphomimetic Ser300 mutations phenocopy TGF-β-dependent inhibition of translation.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, in vivo phosphorylation analysis, in vitro translation assay, cell proliferation assay\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution plus in vivo phosphorylation plus functional translation/proliferation readouts, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"20832312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eEF1Bα disrupts eEF1A-induced actin organization, and eEF1Bα F163 in the domain shared with actin and aa-tRNA binding governs this activity. Combining the F163A lethal mutation with W130A intragenic suppressor or with the K205A mutation dramatically reduces eEF1Bα–eEF1A affinity and restores viability while increasing actin bundling, establishing that eEF1Bα coordinates the dual roles of eEF1A in actin organization and translation.\",\n      \"method\": \"Site-directed mutagenesis, actin bundling assay, nucleotide exchange activity assay, yeast growth phenotype, cell morphology analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus in vitro biochemistry, single lab\",\n      \"pmids\": [\"19095653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eEF1A·GDP (but not eEF1A·GTP) directly activates sphingosine kinase 1 (SK1) in vitro; enhancing cellular eEF1A·GDP levels via TCTP (a GDI) increases SK1 activity in cells. The truncated oncogenic isoform PTI-1, which lacks the G-protein domain, constitutively activates SK1, and SK1 inhibition blocks PTI-1-induced neoplastic transformation.\",\n      \"method\": \"In vitro SK1 activity assay with GTP/GDP-loaded eEF1A, cell-based SK1 activity assay, dominant-negative SK1 and chemical inhibitor rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro activity reconstitution plus cell-based epistasis, single lab\",\n      \"pmids\": [\"20838377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"eEF1A binds the C-terminal domain (CTD) of Gcn2 kinase independently of ribosomes; this interaction is reduced during amino acid starvation and by uncharged tRNAs in vitro. Purified eEF1A inhibits Gcn2-mediated phosphorylation of eIF2α but not Gcn2 autophosphorylation, identifying eEF1A as a Gcn2 inhibitor that modulates the amino acid starvation response.\",\n      \"method\": \"Affinity purification (His-eEF1A), co-immunoprecipitation, GST pulldown with purified proteins, in vitro Gcn2 kinase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — purified protein in vitro kinase assay plus co-IP and pulldown; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21849502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cytoplasmic AID in B cells exists in stoichiometric complex with eEF1A; the interaction depends on the C-terminal domain of eEF1A (not the GTP or tRNA binding regions) and on the AID region responsible for cytosolic retention, establishing eEF1A as a cytosolic retention factor for AID.\",\n      \"method\": \"Endogenous tagging of AID, co-immunoprecipitation, domain mapping, sucrose gradient sedimentation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenously tagged protein (avoiding overexpression artefacts), reciprocal IP, domain mapping; multiple methods, single lab\",\n      \"pmids\": [\"22042842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PUF proteins (FBF) and Argonaute (CSR-1/Ago) form a conserved complex with eEF1A in both C. elegans and mammals; FBF-1–CSR-1 heterodimer inhibits eEF1A GTPase activity in vitro; the mammalian PUM2–Ago–eEF1A complex inhibits translation of reporters after initiation, causing ribosome accumulation within the ORF at the site where the nascent peptide exits the ribosome.\",\n      \"method\": \"Co-immunoprecipitation, recombinant protein pulldown, in vitro GTPase assay, in vitro translation with polysome/ribosome profiling\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro GTPase assay, in vitro translation, co-IP; replicated in two organisms with multiple methods\",\n      \"pmids\": [\"22231398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"eEF1A associates with defective ribosomal products (DRiPs) at the ribosome to generate a signal that triggers aggresome formation upon proteasome inhibition; the Legionella toxin SidI, which inhibits translation but spares this eEF1A function, demonstrated that the aggresome-signaling role of eEF1A is separable from its translation elongation function.\",\n      \"method\": \"siRNA knockdown, aggresome formation assay, SidI toxin pharmacological dissection\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype plus pharmacological tool to separate functions; single lab\",\n      \"pmids\": [\"22357952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"eEF1A binds to Snail transcription factors (via their SNAG domain) when Snail is bound to the E-cadherin promoter, and escorts Snail from the nucleus to the cytoplasm via the Exportin5–aa-tRNA complex; this export is regulated by phosphorylation of Snail, establishing a nuclear role for eEF1A in attenuating transcription factor activity.\",\n      \"method\": \"Co-immunoprecipitation, nuclear export assay, chromatin immunoprecipitation, phosphorylation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, nuclear export functional assay, ChIP; multiple methods; single lab\",\n      \"pmids\": [\"24209753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"eEF1A1 isoform (but not eEF1A2) participates in the entire heat shock response: upon stress it recruits HSF1 to the HSP70 promoter to activate transcription, then associates with elongating RNA Pol II and the HSP70 mRNA 3′UTR to stabilize it and facilitate nuclear-to-ribosome transport. eEF1A1 depletion severely impairs HSR and thermotolerance.\",\n      \"method\": \"siRNA knockdown, ChIP, RNA immunoprecipitation, live-cell imaging, RT-qPCR, thermotolerance assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, RIP, imaging, KD with defined phenotypes) in single rigorous study\",\n      \"pmids\": [\"25233275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"METTL10 trimethylates eEF1A1 at lysine 318 in mammalian cells; siRNA-mediated knockdown of METTL10 decreases eEF1A1 K318 methylation in vivo, as confirmed using a selenium-based SAM analog (ProSeAM) and quantitative MS.\",\n      \"method\": \"ProSeAM chemical probe, affinity purification, quantitative MS, siRNA knockdown, biochemical characterization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — chemical probe plus MS identification plus siRNA loss-of-function confirmation; multiple methods, single lab\",\n      \"pmids\": [\"25144183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"eEF1A is the cytoplasmic retention factor for AID; the mechanism is independent of protein synthesis but requires a tRNA-free form of eEF1A. eEF1A and HSP90 interactions with AID are inversely correlated and define two sequential complexes: HSP90 produces functional AID, which is then stored by eEF1A in the cytoplasm. Inhibiting eEF1A allows AID nuclear accumulation, increasing class switch recombination and chromosomal translocations.\",\n      \"method\": \"Chemical inhibition of eEF1A, co-immunoprecipitation, nuclear export assay, class switch recombination assay, chromosomal translocation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple functional outputs (CSR, translocation), pharmacological and biochemical dissection of two distinct AID complexes; single lab but comprehensive\",\n      \"pmids\": [\"25824822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Direct interaction between eEF1A and HIV-1 reverse transcriptase (RT) has KD ~3–4 nM; both RT thumb and connection domains are required. A single W252A mutation in the RT thumb impairs co-IP with eEF1A and reduces late reverse transcription and virus replication. Didemnin B binds eEF1A and inhibits HIV-1 reverse transcription by >2 logs; W252A RT confers resistance to didemnin B, confirming eEF1A–RT interaction as the antiviral target.\",\n      \"method\": \"Biolayer interferometry, co-immunoprecipitation, site-directed mutagenesis, reverse transcription quantification, virus replication assay, drug resistance analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative binding assay plus mutagenesis plus drug resistance validation; multiple orthogonal methods\",\n      \"pmids\": [\"26624286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FAT10 competes with ubiquitin for binding to the same lysines on eEF1A1, forming FAT10–eEF1A1 complexes instead of Ub–eEF1A1 complexes; FAT10 overexpression therefore decreases eEF1A1 ubiquitination and proteasomal degradation, stabilizing eEF1A1 and promoting cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, lysine mutagenesis, cell proliferation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination competition assay, mutagenesis; single lab\",\n      \"pmids\": [\"27312528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"METTL21B specifically trimethylates eEF1A Lys-165 in an aminoacyl-tRNA- and GTP-dependent manner; this methylation is dynamic and inducible by ER stress. Genetic ablation of METTL21B in mammalian cells alters mRNA translation dynamics and changes codon-specific translation rates as measured by ribosome profiling. METTL21B also accumulates in centrosomes.\",\n      \"method\": \"In vitro methylation assay, in vivo methylation analysis, METTL21B knockout, ribosome profiling, immunofluorescence localization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro enzyme assay, genetic KO with ribosome profiling, GTP/aa-tRNA dependence established; multiple orthogonal methods\",\n      \"pmids\": [\"28108655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A novel 7β-strand KMT (eEF1A-KMT4 / EEF1AKMT4) trimethylates eEF1A at Lys36 in vitro and in vivo; KO of this enzyme in mammalian cells alters translation dynamics and changes translation speed of distinct codons by ribosome profiling.\",\n      \"method\": \"In vitro methylation assay, KO cell lines, ribosome profiling, active site mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme reconstitution, genetic KO, ribosome profiling; multiple methods, single lab\",\n      \"pmids\": [\"28520920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Expanded polyalanine tracts function as nuclear export signals by interacting with eEF1A1; GST-pulldown and MS identified eEF1A1 as the binding partner. Knockdown of eEF1A1 partially corrects cytoplasmic mislocalization of expanded poly(A) proteins and restores their nuclear transcription factor function.\",\n      \"method\": \"GST pulldown/MS, siRNA knockdown, subcellular localization assay, transcriptional reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown/MS plus siRNA loss-of-function with localization and functional readout; single lab\",\n      \"pmids\": [\"28246169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human METTL13 contains two distinct methyltransferase domains: one methylates the eEF1A N-terminus and the other dimethylates Lys55. Structural analysis provided mechanistic detail on N-terminal recognition. Loss of METTL13 function alters translation dynamics and codon-specific translation rates by ribosome profiling.\",\n      \"method\": \"In vitro methylation biochemistry, X-ray crystallography (structural analysis), ribosome profiling, domain mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro biochemistry plus ribosome profiling; multiple orthogonal methods in single study\",\n      \"pmids\": [\"30143613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"METTL13 dimethylates eEF1A Lys55 (eEF1AK55me2) and this modification increases eEF1A's intrinsic GTPase activity in vitro and protein production in cells. METTL13 deletion and loss of eEF1AK55me2 dramatically reduce Ras-driven neoplastic growth in mouse models and patient-derived xenografts.\",\n      \"method\": \"In vitro GTPase assay with methylated vs unmethylated eEF1A, METTL13 KO mouse models, PDX models, metabolic labeling of protein synthesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro GTPase reconstitution plus in vivo mouse and PDX models; multiple orthogonal methods; high-impact journal with rigorous controls\",\n      \"pmids\": [\"30612740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Plitidepsin's antiviral activity against SARS-CoV-2 is mediated through inhibition of host eEF1A; a drug-resistant eEF1A mutant demonstrated this mechanistic link, and plitidepsin reduced viral replication by two orders of magnitude in mouse models.\",\n      \"method\": \"Drug-resistant mutant selection, in vitro antiviral assay, in vivo mouse infection models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — drug-resistant mutant mechanistically validates eEF1A as target, replicated in two mouse models\",\n      \"pmids\": [\"33495306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Single-molecule fluorescence imaging and cryo-EM showed that didemnin B and ternatin-4 both bind to a common site on eEF1A·GTP·aa-tRNA ternary complex and trap eEF1A in an intermediate state of aa-tRNA selection, preventing eEF1A release and aa-tRNA accommodation on the ribosome; the two compounds produce distinct effects on ternary complex dynamics that explain differences in their inhibition efficacy.\",\n      \"method\": \"Single-molecule FRET imaging, cryogenic electron microscopy, in vitro translation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures plus single-molecule dynamics; two orthogonal structural/biophysical approaches in one study\",\n      \"pmids\": [\"36264623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SR-A3 (a ternatin-family cyclic peptide) binds eEF1A with enhanced residence time and rebinding kinetics compared to SS-A3 epimer; single-molecule fluorescence imaging of elongation reactions with purified eEF1A defined the stereospecific binding kinetics. Prolonged target engagement correlated with antitumor efficacy in a Myc-driven mouse lymphoma model.\",\n      \"method\": \"Single-molecule fluorescence imaging (in vitro reconstituted elongation), stereospecific synthesis, in vivo mouse lymphoma model\",\n      \"journal\": \"Nature chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — single-molecule biophysics with purified eEF1A plus in vivo validation; multiple methods, single lab\",\n      \"pmids\": [\"36123449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Tetrahymena eEF1A forms homodimers that bundle F-actin; eEF1A dimers (but not monomers) bind and bundle F-actin at a ~1:1 stoichiometry. Ca²⁺/calmodulin converts eEF1A dimers to monomers, releasing them from actin bundles in a reversible manner, providing a Ca²⁺-dependent regulatory mechanism for actin organization.\",\n      \"method\": \"Gel filtration chromatography, cosedimentation assay, electron microscopy, Ca²⁺/calmodulin treatment\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro biochemical assays with isolated monomer/dimer fractions; single lab with Tetrahymena ortholog\",\n      \"pmids\": [\"16877446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Domain 3 of Tetrahymena eEF1A is the primary F-actin binding domain and influences dimer formation; all three domains bind calmodulin in a Ca²⁺-dependent manner with distinct Ca²⁺ concentration thresholds, with domain 3 serving a pivotal role in Ca²⁺/calmodulin-regulated actin bundling.\",\n      \"method\": \"GST-domain fusion protein binding assays, cosedimentation, calmodulin interaction assay with Ca²⁺ titration\",\n      \"journal\": \"Zoological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion biochemistry with recombinant proteins; single lab, Tetrahymena ortholog\",\n      \"pmids\": [\"18275242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ZPR1 binds preferentially to GDP-bound eEF1A; crystal structure of the ZPR1 domain tandem was determined and structure-based mutational analysis identified a conserved eEF1A-binding epitope required for normal cell growth, proliferation, and cell cycle progression. ZPR1 efficiently displaces eEF1Bα from nucleotide-free eEF1A complexes, suggesting it functions as a negative regulator of eEF1A activation.\",\n      \"method\": \"X-ray crystallography, co-immunoprecipitation, nucleotide exchange displacement assay, site-directed mutagenesis, yeast complementation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure, biochemical displacement assay, mutagenesis with functional complementation; multiple methods in one study\",\n      \"pmids\": [\"17704259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PASKIN kinase interacts with eEF1A1 through its PAS A and kinase domains (binding eEF1A1 C-terminus) and phosphorylates eEF1A1 primarily at Thr432; wild-type but not kinase-inactive PASKIN increases in vitro translation of a reporter cRNA, suggesting that PASKIN-dependent phosphorylation of eEF1A1 promotes translation.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, GST pulldown, in vitro kinase assay, MS, site-directed mutagenesis, in vitro translation assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay with MS identification of phosphosite plus translation readout; single lab\",\n      \"pmids\": [\"17595531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"eEF1A1 (but not eEF1A2) interacts with Ca²⁺/calmodulin; this interaction is predicted by molecular dynamics showing a less flexible calmodulin-binding region in eEF1A1, and confirmed experimentally by ELISA-based binding test. Calmodulin binding interferes with tRNA-binding and actin-bundling activities of eEF1A1 in vitro.\",\n      \"method\": \"Multiple molecular dynamics simulation, ELISA-based calmodulin binding assay, in vitro tRNA binding, in vitro actin bundling assay\",\n      \"journal\": \"BMC structural biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MD simulation plus experimental ELISA binding plus in vitro functional assays; single lab\",\n      \"pmids\": [\"18221514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PKCβI co-immunoprecipitates with eEF1A in the nucleus of insulin-stimulated C2C12 myoblasts and phosphorylates eEF1A2 at Ser53 in vitro; the association between eEF1A2 and PKCβI is dependent on the phosphorylation status of eEF1A2, establishing PKCβI as a nuclear kinase for this elongation factor.\",\n      \"method\": \"Nuclear fractionation, co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, LC-MS/MS proteomics\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus nuclear co-IP plus site mutagenesis; note this abstract focuses on eEF1A2 Ser53 but the nuclear fractionation context includes eEF1A1 identification; single lab\",\n      \"pmids\": [\"20923971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mammalian eEF1A·GDP forms a stable ternary complex with uncharged tRNA (Kd ~20 nM) and a quaternary complex with phenylalanyl-tRNA synthetase (Kd ~9 nM); direct eEF1A–PheRS interaction (Kd ~21 nM) is accelerated by tRNA, supporting a tRNA-channeling model in which the GDP-bound form of eEF1A participates in tRNA delivery to aminoacyl-tRNA synthetase.\",\n      \"method\": \"Gel retardation assay, surface plasmon resonance (BIAcore), fluorescence binding assay\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative binding assays with purified components; single lab\",\n      \"pmids\": [\"12354112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Chp1 is a dedicated ribosome-associated chaperone for eEF1A biogenesis: it is recruited to the ribosome via the nascent polypeptide-associated complex (NAC) during eEF1A synthesis. Absence of Chp1 causes instant proteolysis of nascent eEF1A, widespread protein aggregation, Hsf1 stress activation, and reduced cellular fitness. Chp1 also protects pathogenic eEF1A2 variants linked to epileptic-dyskinetic encephalopathy from degradation.\",\n      \"method\": \"Ribosome association assay, proteomics, protein aggregation assay, Hsf1 reporter assay, fitness assay, pathogenic variant expression\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple functional readouts (proteolysis, aggregation, stress response, fitness) with genetic deletion; single lab but comprehensive mechanistic characterization\",\n      \"pmids\": [\"38360885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Archaeal stalk protein aP1 C-terminal domain (CTD) binds eEF1A·GTP in a space between domains 1 and 3 of eEF1A (crystal structure at 3.0 Å); comparison with the aP1-CTD·eEF1A·GDP structure shows a marked change in binding mode upon GTP/GDP conformational switch, revealing how the stalk supports efficient elongation by engaging eEF1A in both nucleotide states.\",\n      \"method\": \"X-ray crystallography (3.0 Å), biochemical binding assay, in vitro translation assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation; archaeal ortholog; single lab\",\n      \"pmids\": [\"31611569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"eEF1A associates with defective ribosomal products via its translation elongation activity and triggers aggresome formation; the novel eEF1A binding protein IGFN1 (found in yeast two-hybrid screen of human skeletal muscle library) interacts with eEF1A in vitro and is upregulated upon muscle denervation, suggesting it downregulates protein synthesis via eEF1A during denervation.\",\n      \"method\": \"Yeast two-hybrid, in vitro protein interaction confirmation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid plus in vitro confirmation; functional link proposed but not directly demonstrated\",\n      \"pmids\": [\"18756455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"eEF1A1 interacts with eEF1A1 is a cytoplasmic retention factor for AID; the mechanism requires a tRNA-free form of eEF1A confirmed by the functional consequence that inhibiting eEF1A releases AID to the nucleus increasing class switch recombination. (Note: primary mechanistic finding captured under PMID 22042842 and 25824822 above.)\",\n      \"method\": \"Chemical inhibition, nuclear accumulation assay\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — this entry is redundant with 25824822; included here only for completeness; see 25824822 for full detail\",\n      \"pmids\": [\"25824822\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"eEF1A1 is a multifunctional GTPase that in its canonical role delivers aminoacyl-tRNA to the ribosomal A-site (GTP-bound form) and undergoes nucleotide exchange by eEF1Bα (which displaces Mg²⁺ via its switch-region insertion, a mechanism visualized by crystal structures); beyond translation, the GDP-bound form activates sphingosine kinase 1, the protein is phosphorylated by TβR-I at Ser300 to suppress translation and by PASKIN at Thr432, and is extensively trimethylated at multiple lysines (K36 by eEF1A-KMT4, K55 by METTL13 which increases GTPase activity and translational output, K165 by METTL21B in a GTP/aa-tRNA-dependent and inducible manner, K318 by METTL10), with these methylations modulating codon-specific translation rates; eEF1A1 bundles F-actin through dimer formation regulated by Ca²⁺/calmodulin; it acts as a cytosolic retention factor for AID (requiring a tRNA-free form), participates in nuclear export of SNAG transcription factors and TD-NEM-containing proteins via the Exportin5–aa-tRNA pathway, coordinates the heat shock response by recruiting HSF1 to the HSP70 promoter and stabilizing HSP70 mRNA for ribosomal delivery, regulates mRNA stability (e.g., OPN 5′UTR) in an actin-state-dependent manner, inhibits the Gcn2 stress kinase, and interacts directly with HIV-1 RT to support reverse transcription—all while requiring the dedicated ribosome-associated chaperone Chp1 for its own proper co-translational folding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"eEF1A1 is a multifunctional GTPase whose canonical role is the GTP-dependent delivery of aminoacyl-tRNA to the elongating ribosome, a function defined biochemically through its nucleotide-specificity NKMD motif required for GTP hydrolysis and translational fidelity [#2] and structurally through crystal structures of the eEF1A\\u2013eEF1B\\u03b1 complex showing that the exchange factor inserts between the switch regions to destroy the Mg\\u00b2\\u207a-binding site and competes with the CCA-aminoacyl end of tRNA, channeling translation substrates [#0, #1]. Cyclic-peptide inhibitors (didemnin B, ternatin-4, SR-A3) trap eEF1A\\u00b7GTP\\u00b7aa-tRNA ternary complexes in an intermediate state of aa-tRNA selection, defining the drug-binding site and the dynamics of factor release [#31, #32]. eEF1A activity is gated by a network of regulators and modifications: TCTP and ZPR1 act as nucleotide-dissociation inhibitors that favor the GDP-bound form [#4, #35], TGF-\\u03b2 receptor T\\u03b2R-I phosphorylates Ser300 to reduce aa-tRNA binding and suppress translation [#12], and a suite of lysine methyltransferases\\u2014eEF1A-KMT4 (K36), METTL13 (N-terminus and K55), METTL21B (K165), and METTL10 (K318)\\u2014trimethylate the factor to tune codon-specific elongation rates, with METTL13-mediated K55 dimethylation increasing intrinsic GTPase activity and supporting Ras-driven oncogenic growth [#26, #28, #29, #25, #21]. Beyond elongation, eEF1A1 carries diverse moonlighting functions: it bundles F-actin through Ca\\u00b2\\u207a/calmodulin-regulated dimerization [#33, #34, #37], orchestrates the heat shock response by recruiting HSF1 to the HSP70 promoter and stabilizing HSP70 mRNA [#20], exports SNAG-domain transcription factors and TD-NEM/polyalanine-containing proteins from the nucleus via the Exportin5\\u2013aa-tRNA pathway [#7, #19, #27], retains AID in the cytoplasm in a tRNA-free state to limit class switch recombination [#16, #22], inhibits the Gcn2 stress kinase [#15], and in its GDP-bound form activates sphingosine kinase 1 [#14]. eEF1A is co-opted by pathogens, supporting viral RNA replication and HIV-1 reverse transcription [#5, #6, #23] and serving as the host target of antiviral plitidepsin against SARS-CoV-2 [#30]. Its own biogenesis requires the dedicated ribosome-associated chaperone Chp1, recruited via NAC, which protects nascent eEF1A from proteolysis [#40].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that a defined nucleotide-specificity motif governs eEF1A's GTPase chemistry and translational fidelity, anchoring its catalytic identity.\",\n      \"evidence\": \"Site-directed mutagenesis of yeast eEF1A NKMD motif with in vitro poly(U) translation and GTP hydrolysis assays\",\n      \"pmids\": [\"9786872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the full conformational cycle on the ribosome\", \"Yeast ortholog; human residue effects inferred\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the atomic mechanism of guanine-nucleotide exchange, showing eEF1B\\u03b1 drives GDP release by displacing the catalytic Mg\\u00b2\\u207a and competing with aa-tRNA binding.\",\n      \"evidence\": \"Crystal structures of eEF1A\\u2013eEF1B\\u03b1 at 1.67\\u00c5 and of GDP/GDPNP intermediates plus lethal K205A mutagenesis\",\n      \"pmids\": [\"11106763\", \"11373622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Static structures do not capture exchange kinetics in cells\", \"Does not address regulation of exchange by upstream signals\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified ZPR1 (and earlier TCTP) as nucleotide-state-selective regulators that displace the exchange factor and bias eEF1A toward the GDP-bound form, revealing layered control of activation.\",\n      \"evidence\": \"Crystallography, co-IP, nucleotide-exchange displacement assays and yeast complementation; TCTP via Y2H/Co-IP/exchange assay\",\n      \"pmids\": [\"17704259\", \"14623968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological conditions selecting between these regulators unresolved\", \"Connection to specific signaling inputs not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that signaling kinases directly modulate eEF1A translational output, with T\\u03b2R-I phosphorylation of Ser300 suppressing translation and PASKIN phosphorylation of Thr432 promoting it.\",\n      \"evidence\": \"In vitro kinase assays, phosphosite mutagenesis, in vitro translation and proliferation readouts\",\n      \"pmids\": [\"20832312\", \"17595531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between phosphosites not characterized\", \"Phosphatases reversing these marks unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a dedicated lysine-methyltransferase network (eEF1A-KMT4/K36, METTL21B/K165, METTL10/K318) that post-translationally tunes codon-specific elongation rates.\",\n      \"evidence\": \"In vitro methylation assays, enzyme knockouts with ribosome profiling, chemical-probe MS\",\n      \"pmids\": [\"28520920\", \"28108655\", \"25144183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How individual marks integrate to set codon usage is unresolved\", \"Demethylation/turnover of these marks not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that METTL13 methylation of the N-terminus and K55 boosts intrinsic GTPase activity and translational output, linking eEF1A modification to Ras-driven oncogenesis.\",\n      \"evidence\": \"In vitro GTPase assays with methylated eEF1A, crystallography, METTL13 KO mouse and PDX models\",\n      \"pmids\": [\"30143613\", \"30612740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of dependence across tumor genotypes not fully defined\", \"Mechanism linking GTPase rate to growth not dissected at single-codon level\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established eEF1A's actin-bundling moonlighting activity as a Ca\\u00b2\\u207a/calmodulin-regulated, dimer-dependent process distinct from translation.\",\n      \"evidence\": \"Gel filtration, cosedimentation, EM and Ca\\u00b2\\u207a/calmodulin treatment in Tetrahymena; domain mapping; ELISA calmodulin binding\",\n      \"pmids\": [\"16877446\", \"18275242\", \"18221514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely ortholog-based; human in vivo relevance partly inferred\", \"Coordination with translational pool in cells not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed eEF1A1 as a master coordinator of the heat shock response acting at both transcription (HSF1 recruitment) and mRNA stability levels, an isoform-specific nuclear-associated function.\",\n      \"evidence\": \"siRNA knockdown, ChIP, RIP, live-cell imaging and thermotolerance assays\",\n      \"pmids\": [\"25233275\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of HSF1 recruitment by a cytoplasmic factor not structurally defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined eEF1A as a cytoplasmic retention factor and nuclear-export adaptor controlling localization of regulatory proteins, requiring a tRNA-free form for AID retention and the Exportin5\\u2013aa-tRNA route for transcription-factor export.\",\n      \"evidence\": \"Endogenous tagging, co-IP, domain mapping, chemical inhibition with CSR/translocation readouts; export assays for SNAG and TD-NEM/polyalanine proteins\",\n      \"pmids\": [\"25824822\", \"22042842\", \"18799616\", \"24209753\", \"28246169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the same factor distinguishes retention versus export substrates is unresolved\", \"Structural basis of substrate recognition not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Validated eEF1A as the host target of antiviral cyclic peptides and clarified the inhibitory mechanism as trapping of the ternary complex during aa-tRNA selection.\",\n      \"evidence\": \"Drug-resistant mutant selection, cryo-EM and single-molecule FRET, in vivo SARS-CoV-2 and lymphoma models; HIV-1 RT binding via biolayer interferometry\",\n      \"pmids\": [\"33495306\", \"36264623\", \"36123449\", \"26624286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic window between antiviral/antitumor effect and translation toxicity not defined\", \"Selectivity over eEF1A2 not fully addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified Chp1 as a dedicated ribosome-associated chaperone required for eEF1A biogenesis, showing nascent eEF1A needs specialized co-translational protection from degradation.\",\n      \"evidence\": \"Ribosome association, proteomics, aggregation and Hsf1 reporter assays, pathogenic variant expression\",\n      \"pmids\": [\"38360885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Chp1\\u2013nascent eEF1A recognition unknown\", \"Human disease relevance shown for eEF1A2 variants, not eEF1A1\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How eEF1A's many moonlighting roles (actin, nuclear export, stress signaling, viral support) are partitioned from the translational pool within a single cell, and how nucleotide state, modification, and partner availability jointly select among them, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking PTM state to functional partitioning\", \"Quantitative flux between translational and non-translational pools unmeasured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [2, 0, 1, 29]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [5, 6, 11, 39]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [33, 34, 37]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 19, 16]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [2, 12, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 16, 22]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [33, 11]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [17, 31, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2, 29]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [20, 15]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [7, 19, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 30, 29]}\n    ],\n    \"complexes\": [\n      \"eEF1A\\u2013eEF1B\\u03b1 (eEF1B complex)\",\n      \"eEF1A\\u00b7GTP\\u00b7aa-tRNA ternary complex\",\n      \"PUM2\\u2013Ago\\u2013eEF1A complex\"\n    ],\n    \"partners\": [\n      \"EEF1B2\",\n      \"TPT1\",\n      \"ZPR1\",\n      \"METTL13\",\n      \"AICDA\",\n      \"EIF2AK4\",\n      \"SNAI1\",\n      \"VHL\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}