Affinage

EIF2S3

Eukaryotic translation initiation factor 2 subunit 3 · UniProt P41091

Length
472 aa
Mass
51.1 kDa
Annotated
2026-06-09
26 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EIF2S3 encodes eIF2γ, the core GTPase subunit of the heterotrimeric eIF2 complex that delivers initiator Met-tRNAiMet to the 40S ribosomal subunit during translation initiation (PMID:22002225, PMID:23063529). eIF2γ serves as the central scaffold of the trimer: it bridges assembly of the complex by binding eIF2β, whose conserved C-terminal region is sufficient for the interaction (PMID:10769173), and a missense mutation disrupting eIF2β binding compromises complex integrity and start-codon selection fidelity (PMID:23063529); a second eIF2β contact occurs through the zinc-binding domain engaging the guanine nucleotide-binding interface of eIF2γ, an interaction itself required for Met-tRNAiMet binding (PMID:38873976). Domain III of eIF2γ contacts the acceptor stem of Met-tRNAiMet and forms a binding interface with 18S rRNA helix h44, the latter being important for ribosome binding rather than tRNA binding (PMID:22002225). Assembly of the eIF2 trimer requires the ATP-dependent factor Cdc123, which binds eIF2γ domain 3 and controls its abundance, linking eIF2 availability to nutritional and cell-cycle control (PMID:15319434, PMID:37507029). eIF2γ also acts as a platform for eIF2α dephosphorylation and thereby for termination of the integrated stress response: in yeast and Neurospora an N-terminal PP1-binding motif recruits the GLC7/PPP-1 phosphatase (PMID:24706853, PMID:34006661), while in mammals helical repeats of PPP1R15A/GADD34 insert into a hydrophobic groove on eIF2γ to enhance holophosphatase catalytic efficiency (PMID:38547060). Disease-causing EIF2S3 mutations impair eIF2β binding, Met-tRNAiMet binding, or overall eIF2 function and activate the ATF4/ISR stress program, causing the X-linked MEHMO intellectual disability syndrome (PMID:23063529, PMID:30517694, PMID:28055140).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    Established which region of eIF2β mediates its binding to eIF2γ and distinguished this from the related factor eIF5, defining the molecular basis of trimer assembly.

    Evidence Yeast two-hybrid and pull-down domain mapping with comparative sequence analysis

    PMID:10769173

    Open questions at the time
    • No structural resolution of the eIF2β–eIF2γ interface
    • Did not address eIF2α contacts or tRNA binding
  2. 2000 Medium

    Identified eIF2γ as a required cofactor for HCV IRES-mediated translation, implicating it beyond canonical cap-dependent initiation.

    Evidence Hairpin ribozyme library selection against eIF2γ mRNA in HeLa bicistronic IRES reporter cells

    PMID:10900014

    Open questions at the time
    • No direct eIF2γ–IRES binding demonstrated
    • Mechanism of IRES dependence on eIF2γ not defined
  3. 2004 Medium

    Placed eIF2γ downstream of Cdc123, revealing a chaperone that controls eIF2γ abundance and couples translation initiation to nutritional/cell-cycle status.

    Evidence Yeast epistasis analysis and protein abundance measurement in cdc123 mutants

    PMID:15319434

    Open questions at the time
    • Molecular nature of the Cdc123–eIF2γ interaction unresolved
    • Whether Cdc123 acts on assembly vs. stability not distinguished
  4. 2011 High

    Mapped eIF2γ domain III contacts to the Met-tRNAiMet acceptor stem and 18S rRNA helix h44, showing this domain functions in ribosome binding rather than tRNA binding, unlike its EF-Tu counterpart.

    Evidence Directed hydroxyl radical probing and domain III mutagenesis of S. cerevisiae eIF2 on ribosome and tRNA

    PMID:22002225

    Open questions at the time
    • No atomic structure of the full ternary complex on the 40S
    • Contributions of domains I and II to tRNA binding not detailed here
  5. 2012 High

    Demonstrated that eIF2γ is the bridging core of the heterotrimer by showing a missense mutation disrupts eIF2β binding, impairs complex integrity and start-codon selection, and is suppressed by eIF2β overexpression.

    Evidence Biochemical binding assays in human cells plus yeast genetics and suppressor rescue

    PMID:23063529

    Open questions at the time
    • First connection to disease pending mechanistic generalization
    • Structural basis of the disrupted interface not resolved
  6. 2014 High

    Revealed that an N-terminal extension of eIF2γ carries a PP1-binding motif (KKVAF) recruiting GLC7 to dephosphorylate eIF2α, identifying eIF2γ as a platform for ISR termination.

    Evidence Pull-downs, in vivo/in vitro dephosphorylation assays, and genetic rescue with eIF2γ truncation/point mutants in yeast

    PMID:24706853

    Open questions at the time
    • KKVAF motif is yeast-specific; mammalian mechanism unaddressed here
    • Regulation of motif accessibility unknown
  7. 2017 Medium

    Linked an EIF2S3 frameshift allele to severe MEHMO phenotype by showing it elevates ISR activation and impairs eIF2γ function more than missense alleles.

    Evidence Yeast functional comparison of frameshift vs. missense alleles plus phospho-eIF2α markers in patient fibroblasts

    PMID:28055140

    Open questions at the time
    • Precise molecular defect of the frameshift protein not defined
    • Genotype-phenotype correlation based on limited alleles
  8. 2019 High

    Defined the molecular defect of the MEHMO I259M mutation as impaired Met-tRNAiMet binding causing relaxed start-codon selection and ATF4 activation, with tRNAiMet overexpression as rescue.

    Evidence Yeast analog model, in vivo/in vitro tRNA binding assays, near-cognate codon and ATF4 reporter assays in human cells

    PMID:30517694

    Open questions at the time
    • Structural detail of the I259M-affected tRNA interface not resolved
    • Tissue-specific consequences in patients not established
  9. 2019 Medium

    Connected EIF2S3 function to developmental tissues by showing the p.Pro432Ser mutation impairs synthesis and start-codon fidelity, and knockdown increases pancreatic cell death.

    Evidence Yeast fidelity assays, in situ hybridisation of human embryonic tissue, siRNA knockdown with caspase readout

    PMID:30878599

    Open questions at the time
    • Mechanism linking eIF2γ loss to apoptosis not defined
    • Causality for endocrine MEHMO features not established
  10. 2021 Medium

    Extended the eIF2γ-phosphatase recruitment model to a second organism, showing N-terminal deletion of Neurospora eIF2γ elevates phospho-eIF2α and disrupts circadian clock-controlled translation.

    Evidence N-terminal truncation of N. crassa eIF2γ with phospho-eIF2α western blot and circadian oscillator assay

    PMID:34006661

    Open questions at the time
    • Direct PPP-1–eIF2γ binding not biochemically mapped
    • Conservation of N-terminal motif to mammals unaddressed
  11. 2021 Low

    Proposed that a truncated EIF2Bγ isoform alters its interaction with eIF2γ to destabilize the nonproductive eIF2:eIF2B complex.

    Evidence Isoform expression analysis plus structural modeling of the truncated EIF2Bγ–eIF2γ interaction

    PMID:34796993

    Open questions at the time
    • eIF2γ interaction effect is modeled, not biochemically tested
    • Functional consequence in cells not demonstrated
  12. 2023 High

    Provided structural and ATP-dependence detail for eIF2γ assembly by solving the Cdc123–eIF2γ domain 3 complex and showing tightly bound ATP is required for Cdc123-mediated assembly.

    Evidence X-ray crystallography of human Cdc123/eIF2γD3 with thermal shift, yeast viability, and two-hybrid validation

    PMID:37507029

    Open questions at the time
    • Catalytic role of ATP in assembly not enzymatically defined
    • Structure of the full eIF2 trimer with Cdc123 not resolved
  13. 2024 Medium

    Identified a second eIF2β–eIF2γ contact via the eIF2β ZBD engaging the guanine nucleotide-binding interface of eIF2γ, required for Met-tRNAiMet binding.

    Evidence Yeast mutagenesis, co-immunoprecipitation, Met-tRNAiMet binding assays, and intragenic suppressor analysis

    PMID:38873976

    Open questions at the time
    • Structural visualization of the ZBD–eIF2γ interface absent
    • Coupling mechanism to tRNA binding not fully resolved
  14. 2024 High

    Resolved the mammalian basis for eIF2γ-dependent ISR termination by showing PPP1R15A/GADD34 helical repeats insert into a hydrophobic groove on eIF2γ to enhance holophosphatase efficiency.

    Evidence X-ray crystallography, MD simulations, structure prediction, in vitro dephosphorylation, mutagenesis, and cellular assays

    PMID:38547060

    Open questions at the time
    • Whether PPP1R15B uses an analogous eIF2γ contact unaddressed
    • Regulation of this contact during ISR dynamics not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple eIF2γ interfaces (Met-tRNAiMet, eIF2α/β, ribosome h44, Cdc123, and phosphatase recruitment) are spatially and temporally coordinated within a full ribosomal initiation/ISR cycle remains unresolved.
  • No integrated structure spanning ternary complex assembly to ISR termination
  • Mammalian N-terminal phosphatase recruitment vs. GADD34 contact relationship unclear
  • Tissue-specific basis of MEHMO endocrine and neurological features unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0045182 translation regulator activity 3 GO:0060090 molecular adaptor activity 3 GO:0003924 GTPase activity 2
Localization
GO:0005829 cytosol 2 GO:0005840 ribosome 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-9909396 Circadian clock 1
Partners
CDC123EIF2B3EIF2S1EIF2S2GLC7PPP1R15A
Complex memberships
eIF2 heterotrimer (eIF2α/eIF2β/eIF2γ)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 eIF2γ domain III primarily contacts the acceptor stem of Met-tRNAiMet, while domain III also forms a key binding interface with 18S rRNA helix h44 on the 40S ribosomal subunit; unlike the analogous domain III of EF-Tu (which contacts the T stem of tRNA), eIF2γ domain III is important for ribosome binding rather than Met-tRNAiMet binding. Directed hydroxyl radical probing of Saccharomyces cerevisiae eIF2 on the ribosome and on Met-tRNAiMet; biochemical domain III deletion/mutagenesis analyses Nature structural & molecular biology High 22002225
2012 A missense mutation in eIF2γ (EIF2S3) disrupts binding of the eIF2β subunit to eIF2γ, impairing eIF2 complex integrity and translation start codon selection; overexpression of eIF2β suppresses the yeast equivalent of this mutation, establishing eIF2γ as the core subunit bridging the eIF2 heterotrimer. Biochemical studies in human cells overexpressing mutant eIF2γ; yeast genetic system with analogous mutation; suppressor analysis by eIF2β overexpression; in vivo translation start codon selection assay Molecular cell High 23063529
2000 eIF2γ is identified as a cofactor required for HCV IRES-mediated translation; ribozymes targeting eIF2γ mRNA inhibited IRES-driven translation of HCV core protein without affecting cap-dependent translation or cell growth. Randomized hairpin ribozyme library selection in HeLa cells expressing bicistronic HCV IRES reporter; validated with additional ribozymes targeting different eIF2γ mRNA sites Proceedings of the National Academy of Sciences of the United States of America Medium 10900014
2000 The conserved C-terminal region of eIF2β (homologous to archaeal aIF2β, absent from eIF5) is sufficient for binding eIF2γ; eIF5, despite sequence similarity to eIF2β, does not interact with eIF2γ due to a gap in homology in this region. Yeast two-hybrid and co-immunoprecipitation/pull-down assays mapping minimal eIF2β domain sufficient for eIF2γ binding; comparative sequence analysis The Biochemical journal Medium 10769173
2004 In yeast, Cdc123 interacts with eIF2γ (Gcd11) and controls its abundance; loss of Cdc123 depletes eIF2γ and causes cell cycle arrest, establishing a Cdc123–Chf–eIF2γ axis for nutritional control of translation initiation. Yeast genetic analysis (cdc123 mutants, double mutants with chf1/chf2); protein abundance measurements by western blot; genetic interaction mapping placing eIF2γ downstream of Cdc123 The Journal of biological chemistry Medium 15319434
2014 A novel N-terminal extension of yeast eIF2γ contains a PP1-binding motif (KKVAF) that recruits the GLC7 phosphatase to dephosphorylate eIF2α; truncation or point mutation of this motif impairs eIF2α dephosphorylation in vivo and in vitro and enhances GCN4 expression. Pull-down assays; in vivo and in vitro dephosphorylation assays with eIF2γ truncation and point mutants; genetic rescue by replacing N-terminus with alternative GLC7-binding domain; heterologous dimerization domain fusion experiments Proceedings of the National Academy of Sciences of the United States of America High 24706853
2019 The eIF2γ-I259M (MEHMO syndrome) mutation impairs Met-tRNAiMet binding to eIF2 in vivo and in vitro, increases initiation from near-cognate start codons, and activates the ATF4 stress response; overexpression of tRNAiMet rescues Met-tRNAiMet binding and yeast growth defects. Yeast model with analogous eIF2γ-I318M mutation; in vivo and in vitro Met-tRNAiMet binding assays; near-cognate start codon usage assay; ATF4 translation reporter in human cells; tRNAiMet overexpression rescue Nucleic acids research High 30517694
2019 The EIF2S3 p.Pro432Ser mutation impairs protein synthesis and relaxes start codon selection stringency in yeast; EIF2S3 is expressed in developing human pituitary and pancreatic islets, and EIF2S3 knockdown in a pancreatic cell line increases caspase activity/cell death. Yeast functional assays for start codon fidelity; in situ hybridisation on human embryonic tissue; siRNA knockdown in human pancreatic cell line with caspase activity readout EBioMedicine Medium 30878599
2017 The EIF2S3 frameshift mutation (Ile465Serfs) causes increased integrated stress response (ISR) activation in patient fibroblasts and impairs eIF2γ function more severely than tested missense mutations in yeast functional assays, correlating with the more severe MEHMO clinical phenotype. Yeast functional assays comparing frameshift vs. missense eIF2γ alleles; ISR activation measurement (phospho-eIF2α pathway markers) in patient-derived fibroblasts Human mutation Medium 28055140
2023 Crystal structure of human Cdc123 bound to domain 3 of human eIF2γ reveals that eIF2γ domain 3 binds to domain 1 of Cdc123, with the long C-terminal region of Cdc123 linking its ATP and eIF2γ-binding sites; ATP (but not ADP) is tightly bound to Cdc123 and is required for Cdc123-mediated eIF2 assembly. X-ray crystallography of Hs-Cdc123/Hs-eIF2γD3 complex; thermal shift assay; yeast cell viability experiments; western blot; two-hybrid assays Journal of structural biology High 37507029
2024 The N-terminal region of human PPP1R15A (GADD34) beyond its conserved PP1-binding core contains conserved helical repeats with Phe and Trp residues that insert into a hydrophobic groove on the surface of eIF2γ; this eIF2γ–PPP1R15A contact enhances catalytic efficiency of eIF2αP dephosphorylation by the holophosphatase and is required for efficient ISR termination in cells and in vitro. X-ray crystallography; all-atom molecular dynamics simulations; deep learning structure prediction; in vitro dephosphorylation assays; mutagenesis of Phe/Trp residues; cellular functional assays Proceedings of the National Academy of Sciences of the United States of America High 38547060
2024 The zinc-binding domain (ZBD) of eIF2β interacts with eIF2γ via the guanine nucleotide-binding interface of eIF2γ (a second binding site distinct from the previously known α1-helix interaction), and this ZBD–eIF2γ interaction is required for Met-tRNAiMet binding. Yeast mutagenesis of eIF2β ZBD residues and eIF2γ; co-immunoprecipitation binding assays; Met-tRNAiMet binding assays; intragenic suppressor analysis (eIF2βT238A) Bioscience reports Medium 38873976
2021 In Neurospora crassa, deletion of the N-terminal region of eIF2γ (the region required for GLC7/PP1 interaction in yeast) leads to high and arrhythmic phospho-eIF2α levels, demonstrating that eIF2γ recruits the PPP-1 phosphatase to dephosphorylate eIF2α in the context of circadian clock-controlled translation. N-terminal truncation of N. crassa eIF2γ; measurement of phospho-eIF2α levels by western blot; circadian oscillator function assay mBio Medium 34006661
2021 A truncated EIF2Bγ isoform (generated by intronic polyadenylation) is predicted by structural modeling to introduce unfavorable interactions with eIF2γ, potentially decreasing stability of the nonproductive eIF2:EIF2B complex; this isoform is expressed in normal and cancer tissues. Transcript and protein-level analyses confirming IPA isoform expression; structural modeling of truncated EIF2Bγ–eIF2γ interaction Proteins Low 34796993

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Characterization of genes encoding translation initiation factor eIF-2gamma in mouse and human: sex chromosome localization, escape from X-inactivation and evolution. Human molecular genetics 78 9736774
2000 Identification of eIF2Bgamma and eIF2gamma as cofactors of hepatitis C virus internal ribosome entry site-mediated translation using a functional genomics approach. Proceedings of the National Academy of Sciences of the United States of America 75 10900014
2012 eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Molecular cell 72 23063529
2017 EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO. Human mutation 57 28055140
2011 Initiation factor eIF2γ promotes eIF2-GTP-Met-tRNAi(Met) ternary complex binding to the 40S ribosome. Nature structural & molecular biology 50 22002225
2004 Cdc123 and checkpoint forkhead associated with RING proteins control the cell cycle by controlling eIF2gamma abundance. The Journal of biological chemistry 44 15319434
2016 Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. American journal of medical genetics. Part A 43 27333055
2019 Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. EBioMedicine 39 30878599
2004 Phylogenetic mapping of intron positions: a case study of translation initiation factor eIF2gamma. Molecular biology and evolution 38 15356279
1998 Evolutionary relationship between translation initiation factor eIF-2gamma and selenocysteine-specific elongation factor SELB: change of function in translation factors. Journal of molecular evolution 35 9847405
2000 Conserved sequences in the beta subunit of archaeal and eukaryal translation initiation factor 2 (eIF2), absent from eIF5, mediate interaction with eIF2gamma. The Biochemical journal 33 10769173
2014 Protein phosphatase PP1/GLC7 interaction domain in yeast eIF2γ bypasses targeting subunit requirement for eIF2α dephosphorylation. Proceedings of the National Academy of Sciences of the United States of America 26 24706853
2019 MEHMO syndrome mutation EIF2S3-I259M impairs initiator Met-tRNAiMet binding to eukaryotic translation initiation factor eIF2. Nucleic acids research 25 30517694
2000 Two genes become one: the genes encoding heterochromatin protein Su(var)3-9 and translation initiation factor subunit eIF-2gamma are joined to a dicistronic unit in holometabolic insects. Genetics 25 11063691
2018 Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome. Physiological research 23 29303605
2021 Circadian Clock Control of Translation Initiation Factor eIF2α Activity Requires eIF2γ-Dependent Recruitment of Rhythmic PPP-1 Phosphatase in Neurospora crassa. mBio 16 34006661
2022 Cyst stem cell lineage eIF5 non-autonomously prevents testicular germ cell tumor formation via eIF1A/eIF2γ-mediated pre-initiation complex. Stem cell research & therapy 11 35883200
2021 Broadening the phenotypic spectrum and physiological insights related to EIF2S3 variants. Human mutation 7 33942450
2024 Substrate recruitment via eIF2γ enhances catalytic efficiency of a holophosphatase that terminates the integrated stress response. Proceedings of the National Academy of Sciences of the United States of America 5 38547060
2020 Functional characterization of a special dicistronic transcription unit encoding histone methyltransferase su(var)3-9 and translation regulator eIF2γ in Tribolium castaneum. The Biochemical journal 5 32749451
2021 A C-term truncated EIF2Bγ protein encoded by an intronically polyadenylated isoform introduces unfavorable EIF2Bγ-EIF2γ interactions. Proteins 4 34796993
2022 mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome. European journal of medical genetics 3 34999262
2020 Does EIF2S3 Retrogene Activation Regulate Cancer/Testis Antigen Expression in Human Cancers? Frontiers in oncology 3 33330072
2023 Binding of human Cdc123 to eIF2γ. Journal of structural biology 2 37507029
2024 eIF2β zinc-binding domain interacts with the eIF2γ subunit through the guanine nucleotide binding interface to promote Met-tRNAiMet binding. Bioscience reports 1 38873976
2026 Stability and Degradation-based Proteome Profiling Reveals Cannabidiol as a Promising CDC123-eIF2γ Inhibitor for Colorectal Cancer Therapy. Journal of the American Chemical Society 0 41518300

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