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eIF2

Eukaryotic initiation factor 2 (eIF2) is a heterotrimeric GTP-binding protein complex essential for the initiation of mRNA translation in eukaryotic cells, consisting of α, β, and γ subunits that deliver the initiator methionyl-tRNA (Met-tRNAⁱ_Met) to the 40S ribosomal subunit to form the 43S pre-initiation complex.^[1]^[2] The γ subunit of eIF2 serves as the core GTPase, binding GTP and interacting with Met-tRNAⁱ_Met to form a ternary complex, while the α and β subunits modulate tRNA binding affinity and facilitate interactions with other initiation factors.^[2] Assembly of the eIF2 heterotrimer occurs stepwise, involving the chaperone Cdc123, which initially binds the γ subunit to expose sites for α and β subunit attachment, with the α subunit ultimately displacing Cdc123 to complete the complex.^[2] Once formed, eIF2 promotes scanning of the mRNA by the 43S complex from the 5' cap toward the start codon and enhances accurate recognition of the AUG initiation codon, particularly in optimal Kozak contexts.^[2]^[1] A key regulatory mechanism of eIF2 involves phosphorylation of its α subunit at serine 51 by four specialized kinases—PERK (in response to endoplasmic reticulum stress), PKR (viral infection and double-stranded RNA), GCN2 (amino acid starvation), and HRI (oxidative and heme-regulated stress)—which converts eIF2-GDP into a competitive inhibitor of the guanine nucleotide exchange factor eIF2B, thereby attenuating global protein synthesis while selectively enhancing translation of stress-response mRNAs such as ATF4.^[1] This phosphorylation event is central to the integrated stress response (ISR), enabling cellular adaptation to diverse stressors by reducing the energetic burden of translation and reprogramming gene expression to promote survival or apoptosis.^[1] Dysregulation of eIF2 phosphorylation has been implicated in pathologies including cancer, neurodegeneration, and metabolic disorders, underscoring its therapeutic potential.^[1]

Structure

Subunit Composition

Eukaryotic translation initiation factor 2 (eIF2) is a heterotrimeric protein complex composed of three distinct subunits: the α subunit encoded by the EIF2S1 gene with an approximate molecular weight of 36 kDa, the β subunit encoded by the EIF2S2 gene at about 38 kDa, and the γ subunit encoded by the EIF2S3 gene at roughly 52 kDa.^[3]^[4] The complex maintains a fixed stoichiometry of one molecule each of the α, β, and γ subunits, resulting in a total molar mass of approximately 126 kDa.^[5] The α subunit features a key regulatory site at serine 51 (Ser51), which is subject to phosphorylation and plays a critical role in modulating eIF2 activity.^[6] In contrast, the β subunit contains RNA-binding motifs, including a zinc finger-like domain that facilitates interactions with messenger RNA (mRNA) and contributes to the fidelity of translation initiation.^[7] The γ subunit harbors the GTP-binding domain, which exhibits homology to those found in other GTPases and is essential for nucleotide binding and hydrolysis during the initiation process.^[8] This heterotrimeric architecture of eIF2 is highly conserved across eukaryotic organisms, from yeast to humans, underscoring its fundamental importance in the conserved mechanism of protein synthesis initiation.^[9]

Overall Architecture

eIF2 is a heterotrimeric GTPase composed of α, β, and γ subunits that assembles into a compact structure essential for translation initiation, with the α and β subunits flanking the central γ subunit.^[10] The γ subunit, encoded by the EIF2S3 gene and approximately 52 kDa in size, functions as the structural core and primary GTP-binding component, exhibiting homology to elongation factor EF-Tu in its overall fold.^[11] This arrangement positions the γ subunit to coordinate nucleotide binding while the flanking α (36 kDa) and β (38 kDa) subunits, encoded by EIF2S1 and EIF2S2 respectively, contribute to regulatory interactions without direct GTP contact.^[10] The GTPase-like domain of the γ subunit resides primarily in its N-terminal G domain (domain I), which contains a nucleotide-binding pocket characterized by conserved motifs including the P-loop (GxxxxGK[S/T]) for phosphate coordination and the G4 motif for guanine recognition. Switch regions I (residues ~60-80) and II (~100-120) flank this pocket, undergoing conformational rearrangements upon GTP hydrolysis to facilitate factor release; in the nucleotide-free state, the pocket splays open with an RMSD shift of ~12 Å relative to GTP-bound forms, enabling guanine nucleotide exchange. Key residues within the γ subunit, such as Lys48 and Asp64, participate in GTP coordination by stabilizing the magnesium ion and phosphate groups in the binding pocket, as revealed by the 2.4 Å X-ray structure of human eIF2γ.^[11] Inter-subunit interfaces primarily involve hydrophobic and electrostatic contacts between the α subunit's C-terminal domain and the γ subunit's domain II, as well as the β subunit's N-terminal helix and zinc-binding domain interacting near the γ nucleotide site, thereby stabilizing the heterotrimer.^[10] These interfaces exhibit partial flexibility, with cryo-EM structures from 2019 demonstrating domain mobility, including a ~46° elbow-like rotation in the α subunit relative to γ and unconstrained positioning of the β subunit.^[6] NMR studies further support this mobility, showing limited but significant rearrangement (~15°) between GTP- and GDP-bound states in the γ domain, contrasting with more rigid elongation factors.^[10] Recent cryo-EM structures (as of 2025) have further elucidated eIF2's conformational dynamics in complexes with eIF2B and regulatory proteins.^[12]^[13]

Function

Ternary Complex Formation

The formation of the ternary complex (TC) begins with the heterotrimeric eIF2 binding guanosine triphosphate (GTP) primarily through its γ subunit, which harbors the GTP-binding site analogous to other translational GTPases.^[14] This GTP-bound eIF2 then recruits the initiator methionyl-transfer RNA (Met-tRNAⁱ_Met) to the γ subunit's tRNA-binding site located in domain II, establishing a stable interaction at the tRNA's 3' acceptor end.^[15] The sequential assembly—eIF2-GTP first, followed by Met-tRNAⁱ_Met—ensures efficient TC formation in the cytoplasm, a critical early step in delivering the initiator tRNA to the ribosome.^[14] Key subunit-specific interactions stabilize the TC. The β subunit's N-terminal region, featuring positively charged lysine- and arginine-rich motifs, contacts the anticodon stem-loop of Met-tRNAⁱ_Met, enhancing recognition and binding specificity despite its auxiliary role compared to γ.^[16] Meanwhile, the α subunit stabilizes the overall ternary complex and modulates interactions with other initiation factors, while the γ subunit forms the primary interface with the tRNA's acceptor arm. These interactions collectively position Met-tRNAⁱ_Met in an extended conformation suitable for subsequent ribosomal delivery.^[17] The GTP-bound conformation of eIF2 is essential for promoting stable TC assembly, as the nucleotide facilitates conformational changes in the γ subunit that optimize the tRNA-binding pocket and increase affinity for Met-tRNAⁱ_Met by up to 13-fold through recognition of the methionylated CCA end.^[15] This energy-dependent stabilization yields a high-affinity complex with an apparent dissociation constant (K_d) of approximately 20 nM for wild-type eIF2, underscoring its role as a prerequisite for efficient translation initiation under basal conditions.^[17]

Delivery to Ribosome

The eukaryotic initiation factor 2 (eIF2) ternary complex (TC), consisting of eIF2 bound to GTP and initiator methionyl-tRNA (Met-tRNAⁱ_Met), associates with the 43S pre-initiation complex to facilitate translation initiation. The 43S complex comprises the 40S ribosomal subunit along with eIF1, eIF1A, eIF3, and eIF5, and the TC binds to this assembly primarily through interactions between the α-subunit of eIF2 and the 40S subunit, positioning Met-tRNAⁱ_Met in a P/I hybrid site orientation that orients the anticodon for mRNA engagement.^[18] This association stabilizes the pre-initiation complex (PIC), enabling subsequent recruitment of mRNA to form the 48S initiation complex.^[18] Upon mRNA recruitment near the 5' cap structure by eIF4F, the TC promotes attachment of the 40S subunit to the mRNA, initiating the scanning process. During scanning, the PIC moves downstream from the 5' end, with the Met-tRNAⁱ_Met anticodon probing potential start codons in an open ribosomal conformation that allows mRNA threading through the entry channel.^[19] The TC, via eIF2, maintains the tRNA in a configuration conducive to base-pairing interactions, ensuring efficient progression along the 5' untranslated region (UTR). Recognition of the start AUG codon occurs through anticodon-codon pairing between the Met-tRNAⁱ_Met and the mRNA AUG, which is stabilized by eIF2's positioning of the tRNA within the P-site decoding center. This interaction triggers conformational rearrangements in the PIC, including closure of the 40S subunit's mRNA entry latch and rotation of the head domain, transitioning from an open scanning state to a closed accommodation state that secures the mRNA and tRNA. The TC-induced opening facilitates unidirectional mRNA threading during scanning, preventing slippage and promoting accurate positioning. eIF2 contributes to the fidelity of start site selection by enforcing stringent anticodon-codon matching, thereby discriminating against non-AUG codons and reducing initiation at suboptimal sites. Disruptions in eIF2 function can compromise start site fidelity, leading to increased leaky scanning; specific mutations in subunits like β or γ have been shown to affect discrimination against non-AUG codons.^[20]^[19] This role ensures that translation typically begins at the appropriate AUG, maintaining translational accuracy across eukaryotic systems.^[21]

Regulation

eIF2α Phosphorylation

Phosphorylation of the eukaryotic initiation factor 2 (eIF2) α subunit at serine 51 (Ser51) serves as a key regulatory mechanism in response to cellular stress, modulating global protein synthesis. This post-translational modification is catalyzed by four specialized kinases, each responsive to distinct stressors, and results in the conversion of eIF2-GDP into a potent competitive inhibitor of the guanine nucleotide exchange factor eIF2B.^[1] By increasing the affinity of phosphorylated eIF2-GDP for eIF2B approximately 10-fold, this process sequesters eIF2B, thereby inhibiting the recycling of eIF2 to its active GTP-bound form and drastically curtailing ternary complex (eIF2-GTP-Met-tRNAi) formation essential for translation initiation.^[22] Under severe stress conditions, this leads to a profound suppression of overall translation while selectively enhancing the synthesis of stress-response factors.^[1] The four eIF2α kinases—heme-regulated inhibitor (HRI), protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), and general control nonderepressible 2 (GCN2)—are activated by specific environmental cues. HRI (also known as EIF2AK1) is primarily triggered by heme deficiency or oxidative stress; under low heme conditions, heme dissociates from HRI's kinase insert domain, promoting autophosphorylation and kinase activation.^[23] PKR (EIF2AK2) responds to viral double-stranded RNA (dsRNA), where dsRNA binding to its two N-terminal dsRNA-binding domains induces dimerization, autophosphorylation at threonine 446, and subsequent eIF2α phosphorylation to halt viral protein production.^[1] PERK (EIF2AK3), a transmembrane kinase localized to the endoplasmic reticulum (ER), senses unfolded protein accumulation during ER stress; this causes dissociation from the chaperone BiP, leading to PERK oligomerization, autophosphorylation at threonine 980, and activation of the unfolded protein response branch.^[1] GCN2 (EIF2AK4) detects amino acid deprivation through binding of uncharged tRNAs to its histidyl-tRNA synthetase-related domain, inducing a conformational change, autophosphorylation at threonines 882 and 887, and kinase activity; it also responds to UV irradiation.^[1] Collectively, these kinases converge on eIF2α phosphorylation to orchestrate the integrated stress response (ISR), a conserved cytoprotective pathway that attenuates general protein synthesis to conserve resources and redirect translation toward adaptive genes, such as those encoding transcription factor ATF4 via upstream open reading frames.^[22] Despite their diverse activation mechanisms and stressors—ranging from oxidative damage and viral infection to nutrient scarcity and proteotoxic stress—the ISR unifies cellular adaptation, promoting survival under transient challenges but potentially triggering apoptosis if stress persists.^[23] This regulatory strategy underscores eIF2α phosphorylation's role as a central hub for stress signaling in vertebrates, with no additional eIF2α kinases identified beyond these four.^[23]

Guanine Nucleotide Exchange

eIF2B serves as the guanine nucleotide exchange factor (GEF) for eIF2, operating as a heteropentameric complex comprising α, β, γ, δ, and ε subunits. The γ and ε subunits catalyze the release of GDP from the γ subunit of eIF2, enabling the binding of GTP to regenerate the active eIF2-GTP form required for translation initiation.^[24]^[25] The core exchange cycle proceeds as eIF2-GDP binds to eIF2B, facilitating GDP dissociation followed by GTP association and release of eIF2-GTP, thereby recycling eIF2 for subsequent rounds of initiation. This nucleotide exchange represents the rate-limiting step in translation initiation, ensuring controlled protein synthesis under normal conditions.^[26]^[27] Phosphorylation on the α subunit of eIF2 (eIF2α-P) potently inhibits this process by enhancing eIF2's affinity for eIF2B approximately 10-fold (Kd ≈ 3.5 nM for eIF2α-P versus 32 nM for unphosphorylated eIF2), resulting in a stable dead-end complex that sequesters eIF2B and blocks further GDP release.^[22] This inhibition dramatically reduces the exchange rate, effectively halting eIF2 recycling and global translation.^[28]^[29] The small molecule ISRIB acts as a regulatory modifier by allosterically antagonizing the phospho-eIF2/eIF2B interaction, thereby restoring nucleotide exchange activity and countering the inhibitory effects of eIF2α phosphorylation.^[30]

Pathophysiology

Dysregulation in Disease

Dysregulation of eIF2, particularly through hyperactivation of the integrated stress response (ISR) via chronic phosphorylation of its α subunit (eIF2α), contributes to neuronal loss in several neurodegenerative disorders. In Alzheimer's disease (AD), sustained PERK-mediated eIF2α phosphorylation elevates ATF4 expression, promoting synaptic dysfunction and neuronal apoptosis in response to amyloid-β accumulation and endoplasmic reticulum (ER) stress.^[31] Similar chronic eIF2α phosphorylation via PERK occurs in Parkinson's disease (PD), where it disrupts dopamine neuron function and exacerbates α-synuclein toxicity, leading to motor impairments.^[32] In amyotrophic lateral sclerosis (ALS), hyperactive ISR signaling, including PERK-eIF2α activation, drives motor neuron degeneration through ATF4-dependent pro-apoptotic pathways, as observed in patient-derived models and postmortem tissues.^[33] In metabolic disorders, eIF2 dysregulation manifests through kinase-specific hyperactivity that impairs cellular homeostasis. GCN2-mediated eIF2α phosphorylation is hyperactivated in pancreatic β-cells under amino acid stress in type 2 diabetes, triggering ATF4 and CHOP expression that culminates in β-cell apoptosis and reduced insulin secretion.^[34] Conversely, in hemolytic anemias such as those associated with heme deficiency, the heme-regulated inhibitor (HRI) kinase induces eIF2α phosphorylation to curtail globin synthesis, but defects in HRI signaling exacerbate oxidative damage and erythroid precursor death, worsening anemia severity.^[35]^[36] eIF2 dysregulation plays a dual role in cancer, often favoring tumor progression by evading stress responses. PKR, an eIF2α kinase, acts as a tumor suppressor, and its downregulation in various cancers promotes proliferation. Hypo-phosphorylation of eIF2α, through reduced kinase activity or enhanced dephosphorylation, sustains high global translation rates essential for tumor growth and metastasis, as seen in breast and lung cancers where ISR inhibition correlates with aggressive phenotypes.^[37] During viral infections, eIF2α phosphorylation serves as a host defense mechanism to halt viral protein synthesis, but many viruses counteract this through targeted inhibitors. Herpes simplex virus (HSV-1) encodes the γ34.5 protein, which recruits protein phosphatase 1 to dephosphorylate eIF2α, thereby restoring translation and facilitating viral replication in infected cells.^[38] This evasion of PKR-induced eIF2α phosphorylation allows HSV-1 to propagate despite the host's ISR activation.^[39] Rare genetic mutations directly or indirectly perturb eIF2 function, leading to severe disorders. Mutations in eIF2S genes encoding eIF2 subunits are exceedingly rare and typically incompatible with life, with limited reports of heterozygous variants causing mild translational defects.^[40] More commonly, mutations in eIF2B subunits, as in vanishing white matter disease (VWMD), impair guanine nucleotide exchange on eIF2, indirectly amplifying ISR hypersensitivity to stress and resulting in oligodendrocyte dysfunction, hypomyelination, and progressive neurological decline.^[41] Recent studies have linked ISR dysregulation to neuropsychiatric conditions, including major depressive disorder. Post-2020 research indicates defective regulation of the eIF2-eIF2B translational axis in major depressive disorder, contributing to its pathophysiology.^[42]

Emerging Therapeutic Targets

ISRIB, a small molecule that alleviates the inhibitory effects of phosphorylated eIF2 on translation by stabilizing eIF2B activity, has shown promise in preclinical models of Alzheimer's disease (AD). In transgenic AD mouse models, ISRIB administration restored protein synthesis deficits, improved synaptic plasticity, and enhanced memory performance without altering amyloid-beta pathology. Derivatives of ISRIB, such as optimized analogs with improved pharmacokinetics, have similarly reduced tau hyperphosphorylation and associated neuropathology in tauopathy mouse models by counteracting chronic integrated stress response (ISR) activation.^[43]^[44]^[45] Kinase inhibitors targeting eIF2 regulatory pathways represent another therapeutic avenue, particularly for neurodegeneration and viral infections. The PERK inhibitor GSK2606414 has demonstrated neuroprotective effects in models of Parkinson's disease and tau-mediated frontotemporal dementia by blocking eIF2α phosphorylation and preventing neuronal loss, though pancreatic toxicity limits its clinical translation. For antiviral applications, modulators of PKR, such as small molecules that enhance PKR activation or inhibit viral countermeasures, potentiate the ISR to suppress replication of viruses like HIV and Zika by promoting eIF2α phosphorylation and translation shutdown.^[46]^[33]^[47]^[48] eIF2B activators offer targeted relief for leukodystrophies like vanishing white matter disease (VWMD), caused by eIF2B mutations that impair guanine nucleotide exchange factor (GEF) activity. Compounds like ISRIB and the investigational DNL343 enhance eIF2B catalytic function, rescuing mutant eIF2B stability and neurological deficits in VWMD mouse models by boosting translation under stress. Gene therapy approaches, including CRISPR-Cas9 editing of the eIF2S1 gene to mutate Ser51 to alanine, hold prospects for chronic ISR conditions by preventing eIF2α phosphorylation and restoring basal translation rates, as demonstrated in cell models resistant to stress-induced shutdown.^[49]^[50]^[51] As of 2025, clinical trials for ISRIB analogs in amyotrophic lateral sclerosis (ALS) have advanced to phase II/III evaluation, with DNL343 tested in the HEALEY ALS Platform Trial (Regimen G) showing CNS penetration and ISR modulation but failing to meet primary efficacy endpoints for disease progression, highlighting challenges like off-target effects on global translation and potential toxicity from excessive protein synthesis. Phospho-eIF2α levels serve as a promising biomarker in cancer and metabolic diseases; elevated phosphorylation correlates with poor prognosis in lung and renal cell carcinomas, while in diabetes models, it indicates ISR-driven insulin resistance, enabling patient stratification for ISR-targeted therapies.^[52]^[53]^[54]^[55]^[56]

References

[1]
The eIF2α kinases: their structures and functions - PMC
Cell signaling in response to an array of diverse stress stimuli converges on the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2).
[2]
Stepwise assembly of the eukaryotic translation initiation factor 2 ...
eIF2 guides the initiator tRNA to the ribosome, participates in scanning of the mRNA molecule, supports selection of the start codon, and modulates the ...
[3]
eIF2alpha/EIF2S1 General Information - Sino Biological
EIF2 is composed of 3 nonidentical subunits, the 36-kD EIF2-alpha subunit (EIF2S1), the 38-kD EIF2-beta subunit (EIF2S2; 603908), and the 52-kD EIF2-gamma ...Missing: weights | Show results with:weights
[4]
p41091 · if2g_human - UniProt
Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain (PubMed: ...
[5]
Phosphorylation Stoichiometries of Human Eukaryotic Initiation ...
Jun 27, 2014 · As eIF2 is a heterotrimer with a molecular mass of 126 kDa, we analyzed the two factors that have been previously reported as phosphorylated ...Missing: total | Show results with:total
[6]
The structural basis of translational control by eIF2 phosphorylation
May 13, 2019 · In response to a wide range of signals, multiple protein kinases phosphorylate a single serine, historically known as Ser51, within the eIF2α ...
[7]
The β Subunit of Eukaryotic Translation Initiation Factor 2 Binds ...
We report here the ability of eIF2β to bind mRNA in vitro and show that this binding is dependent on both the amino and carboxyl domains of the protein, ...
[8]
The archaeal eIF2 homologue: functional properties of an ancient ...
These results indicated that the G-domain on the γ-subunit is fully competent for nucleotide binding and that binding is not affected by either the α- or β- ...
[9]
Evolutionary Conservation of Reactions in Translation - PMC
The ternary complex that is formed, Met-tRNAi-GTP-eIF2 in eukaryotes, is catalyzed by eIF2, although this protein is composed of three subunits; the γ subunit ...
[10]
X-ray structure of translation initiation factor eIF2gamma - PubMed
Mar 12, 2004 · The x-ray structure of the gamma-subunit of the heterotrimeric translation initiation factor eIF2 has been determined to 2.4-A resolution.
[11]
[PDF] Translation initiation: structures, mechanisms and evolution
y20-fold lower than that of eIF2.GTP. Furthermore, the affinities of both eIF2.GTP and ... A second conserved lysine, K48 proposed to have a role in catalysis ( ...
[12]
eIF2 interactions with initiator tRNA and eIF2B are regulated by post ...
Aug 11, 2015 · We propose that modifications of these unstructured regions have a key role in regulating interactions between eIF2 and eIF2B, as well as other eIFs.
[13]
Initiation Factor eIF2γ Promotes eIF2–GTP–Met-tRNAiMet Ternary ...
Our results identify a key binding-interface between domain III of eIF2γ and 18S rRNA helix h44 on the 40S subunit. Moreover, we showed that eIF2γ primarily ...Missing: homologous | Show results with:homologous
[14]
Roles of yeast eIF2α and eIF2β subunits in the binding of the initiator ...
Nov 26, 2012 · X-ray structure of translation initiation factor eIF2gamma: implications for tRNA and eIF2alpha binding. ,. J. Biol. Chem. ,. 2004. , vol. 279.<|control11|><|separator|>
[15]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3210414/
[16]
The structure of a human translation initiation complex reveals two ...
Jan 29, 2024 · Human eukaryotic initiation factor 2 (eIF2)–GTP–Met–tRNAi ternary complex and eIF3 stabilize the 43S preinitiation complex. J. Biol. Chem ...
[17]
Selection of start codon during mRNA scanning in eukaryotic ...
Jun 15, 2022 · The study highlights how the scanning conformation of ribosomal 48S PIC acts as a coarse selectivity checkpoint for start codon selection and scans long 5′ ...
[18]
Cryo-EM study of start codon selection during archaeal translation ...
Nov 7, 2016 · AUG recognition stops scanning, leads to factor release and to the assembly of an elongation-proficient 80S complex through large subunit ...
[19]
Structural basis for translational control by the human 48S initiation ...
Sep 17, 2024 · The majority of 48S complexes progress beyond the near-cognate AUC codon to the downstream AUG, resulting in start codon recognition and GTP ...
[20]
The integrated stress response: From mechanism to disease - PMC
Early studies showed that inhibition of either the PKR branch of the ISR or phosphorylation of eIF2 led to transformation of mouse fibroblasts and increased ...
[21]
Integrated stress response of vertebrates is regulated by four eIF2α ...
Sep 16, 2016 · The integrated stress response (ISR) is a cytoprotective pathway initiated upon phosphorylation of the eukaryotic translation initiation ...Missing: consequences | Show results with:consequences
[22]
Critical Contacts between the Eukaryotic Initiation Factor 2B (eIF2B ...
Central to the initiation process is the GTP binding protein eIF2, which delivers aminoacylated initiator methionyl tRNA ( ... Structural switch of the γ subunit ...Missing: Lys48 Asp64
[23]
eIF2B localization and its regulation during the integrated stress ...
Sep 20, 2024 · The γ and ε subunits catalyze the GEF activity, whereas the α, β and δ subunits regulate this activity in response to different cellular stress ...
[24]
eIF2B Mechanisms of Action and Regulation: A Thermodynamic View
eIF2B catalyzes nucleotide exchange and Met-tRNAi binding to form a new TC. Phosphorylation of the α subunit of eIF2 by several stress-activated kinases turns ...
[25]
eIF2 independently binds two distinct eIF2B subcomplexes that ...
We show that an eIF2B subcomplex of the GCN3, GCD7, and GCD2 subunits binds to eIF2 and has a higher affinity for eIF2(αP), but it lacks nucleotide-exchange ...
[26]
[PDF] The Structural Basis of Translational Control by eIF2 Phosphorylation
Dec 20, 2018 · As phosphorylated eIF2 has ten-fold higher affinity for eIF2B than unphosphorylated. eIF2 (Kd, 3.5 nM vs 32.2 nM)3, we first focused on this ...
[27]
eIF2 independently binds two distinct eIF2B subcomplexes that ...
We have used an in vitro nucleotide-exchange assay to show that wild-type yeast eIF2B is inhibited by phosphorylated eIF2 [eIF2(alphaP)] and to characterize ...
[28]
Regulation and function of elF2B in neurological and metabolic ...
Jun 20, 2022 · Given eIF2B's role as a GEF for eIF2, eIF2B bodies were hypothesised to be sites of eIF2B GEF activity, required for translation initiation.
[29]
Binding of ISRIB reveals a regulatory site in the nucleotide ... - Science
Mar 30, 2018 · ISRIB action converges on eukaryotic translation initiation factor 2B (eIF2B), a protein complex with guanine nucleotide exchange factor (GEF) ...
[30]
Roles of eIF2α kinases in the pathogenesis of Alzheimer's disease
Generally, PERK-dependent eIF2α phosphorylation is thought to block global translation initiation and in this manner can alleviate ER stress by reducing the ...
[31]
Cell-type-specific disruption of PERK-eIF2α signaling in ...
Taken together, our findings show that proper regulation of PERK-eIF2α signaling in DA neurons is required for normal cognitive and motor function in a non- ...
[32]
PERK inhibition prevents tau-mediated neurodegeneration in a ...
Oct 8, 2015 · Increased PERK-P and eIF2α-P have been reported in postmortem analyses of brains from patients with Alzheimer's disease (AD), Parkinson's ...<|separator|>
[33]
Endoplasmic reticulum stress and eIF2α phosphorylation - PubMed
Jul 12, 2017 · Pancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data.
[34]
Heme‐regulated eIF2α kinase (HRI) is required for translational ...
We establish that HRI, which is expressed predominantly in erythroid cells, regulates the synthesis of both α‐ and β‐globins in red blood cell (RBC) precursors.Results · Mild Macrocytosis And... · Eif2α Kinases As Specific...
[35]
Heme-regulated eIF2α kinase in erythropoiesis and ...
Heme-regulated eIF2α kinase, also known as heme-regulated inhibitor (HRI), is a key heme-binding protein that senses intracellular heme concentrations.Atf4 And Eif2αp Are... · Hri-Atf4 Is Necessary For... · Hri-Atf4--Mediated Grb10...
[36]
Inhibition of PKR by Viruses - Frontiers
Eukaryotic translation initiation factor 2 alpha kinase 2, better known as PKR, acts as both a sensor and an effector in the response to viral infections. After ...
[37]
Protein translation: biological processes and therapeutic strategies ...
Feb 23, 2024 · In this review, we discuss how deregulated translation can lead to aberrant protein synthesis, altered cellular functions, and disease ...
[38]
Enhanced antitumor efficacy of a herpes simplex virus ... - PNAS
In the absence of the γ34.5 protein, the cellular PKR kinase is activated, phosphorylated eIF2 accumulates, and the initiation of protein synthesis is blocked ( ...
[39]
The role of host eIF2α in viral infection - Virology Journal
Jul 23, 2020 · eIF2 is a heterotrimer composed of α, β and γ subunits, and its activity is regulated by phosphorylation of its α subunit at Ser51. Once ...
[40]
eIF2B and the Integrated Stress Response - PubMed Central - NIH
Mutations that inhibit the induction of ISR in response to amino acid depletion are called General amino acid control nonderepressible (Gcn−).Missing: VWMD schizophrenia
[41]
Vanishing white matter disease expression of truncated EIF2B5 ...
Dec 10, 2020 · PERK is one of the stress-responsive kinases that activate the ISR via phosphorylation of eIF2. PERK misexpression caused hypomyelination, ...Missing: VWMD schizophrenia
[42]
Defective regulation of the eIF2-eIF2B translational axis underlies ...
Oct 1, 2024 · Taken together, results suggest that impaired the eIF2-eIF2B axis participates in the pathophysiology of MDD, and underscore eIF2-linked ...
[43]
Correction of eIF2-dependent defects in brain protein synthesis ...
Feb 2, 2021 · The compound ISRIB blocks the translation inhibition arm of the ISR but failed to confer cognitive benefit and caused mortality in mouse models ...
[44]
Correction of eIF2-dependent defects in brain protein synthesis ...
ISRIB restores synapse function and memory in a transgenic mouse model of AD. Next, we investigated whether ISR inhibition could reverse deficits in synaptic ...
[45]
The integrated stress response in neurodegenerative diseases
Feb 19, 2025 · Additionally, it was found that activation of PERK-eIF2α contributed to the pathological phosphorylation of tau in rTg4510 mice, a mouse model ...
[46]
Targeting PERK signaling with the small molecule GSK2606414 ...
Jan 31, 2018 · Targeting PERK signaling with the small molecule GSK2606414 prevents neurodegeneration in a model of Parkinson's disease ... eIF-2 Kinase / ...
[47]
a strategy to overcome the antiviral effect of protein kinase PKR - PMC
The double-stranded RNA (dsRNA)-activated PKR has been implicated in antiviral defense due to its ability to respond to viral infection. PKR binds to and is ...
[48]
The small molecule ISRIB rescues the stability and activity of ... - eLife
Feb 28, 2018 · ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels.<|separator|>
[49]
Investigational eIF2B activator DNL343 modulates the integrated ...
Aug 18, 2025 · Here we demonstrate that a CNS penetrant small molecule eIF2B activator inhibits the ISR in cellular models of ALS and the brain of an inducible ...
[50]
Paradoxical Sensitivity to an Integrated Stress Response Blocking ...
Nov 3, 2016 · CRISPR-Cas9 guides targeting the EIF2S1/eIF2α locus were transfected alongside a repair template with a Ser 51 to Ala mutation in eIF2α that ...Missing: therapy chronic
[51]
DNL343 Falls Short of Primary End Point in Phase 2/3 HEALEY-ALS ...
Jan 7, 2025 · DNL343 (Denali Therapeutics), an investigational eIF2B agonist in development for amyotrophic lateral sclerosis (ALS), did not meet its primary end point.
[52]
https://www.neurologylive.com/view/dnl343-falls-short-primary-end-point-phase-2-3-healey-als-platform-trial
[53]
TIPRL potentiates survival of lung cancer by inducing autophagy ...
Dec 20, 2019 · In addition, TIPRL overexpression and high levels of eIF2α phosphorylation were positively correlated with the malignancy of the cancer.
[54]
Prognostic role of eIF2α protein in metastatic renal cell cancer patients
Jun 11, 2025 · Based on these results, we suggest that eIF2α may serve as a novel biomarker to predict survival and treatment response in metastatic RCC patients.
[55]
Translation Regulation by eIF2α Phosphorylation and mTORC1 ...
Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs.