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- PDB-9hvf: Native human PPP1R15B-P-eIF2-eIF2B complex -

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Basic information

Entry
Database: PDB / ID: 9hvf
TitleNative human PPP1R15B-P-eIF2-eIF2B complex
Components
  • Eukaryotic translation initiation factor 2 subunit 1
  • Eukaryotic translation initiation factor 2 subunit 2
  • Eukaryotic translation initiation factor 2 subunit 3
  • Protein phosphatase 1 regulatory subunit 15B
  • Translation initiation factor eIF-2B subunit gamma
KeywordsTRANSLATION / phosphorylation / Eukaryotic Initiation Factor-2B / Eukaryotic Initiation Factor-2
Function / homology
Function and homology information


male germ cell proliferation / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / Response of EIF2AK1 (HRI) to heme deficiency ...male germ cell proliferation / translation initiation ternary complex / regulation of translation in response to endoplasmic reticulum stress / glial limiting end-foot / HRI-mediated signaling / eukaryotic translation initiation factor 2B complex / response to manganese-induced endoplasmic reticulum stress / Cellular response to mitochondrial stress / positive regulation of type B pancreatic cell apoptotic process / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / methionyl-initiator methionine tRNA binding / negative regulation of translational initiation in response to stress / protein phosphatase type 1 complex / PERK-mediated unfolded protein response / PERK regulates gene expression / response to kainic acid / eukaryotic translation initiation factor 2 complex / cytoplasmic translational initiation / regulation of translational initiation in response to stress / translation factor activity, RNA binding / formation of translation preinitiation complex / protein phosphatase regulator activity / guanyl-nucleotide exchange factor complex / eukaryotic 48S preinitiation complex / oligodendrocyte development / protein-synthesizing GTPase / Formation of the ternary complex, and subsequently, the 43S complex / ER overload response / Ribosomal scanning and start codon recognition / Translation initiation complex formation / negative regulation of PERK-mediated unfolded protein response / negative regulation of protein phosphorylation / Response of EIF2AK4 (GCN2) to amino acid deficiency / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / response to glucose / mitophagy / translation initiation factor binding / translation initiation factor activity / stress granule assembly / cellular response to amino acid starvation / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / translational initiation / response to hydrogen peroxide / response to peptide hormone / PKR-mediated signaling / ABC-family proteins mediated transport / male gonad development / cytoplasmic stress granule / cellular response to UV / T cell receptor signaling pathway / regulation of translation / cellular response to heat / ribosome binding / response to heat / cellular response to oxidative stress / in utero embryonic development / cadherin binding / GTPase activity / mRNA binding / synapse / GTP binding / endoplasmic reticulum / mitochondrion / RNA binding / extracellular exosome / zinc ion binding / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
Protein phosphatase 1, regulatory subunit 15B, N-terminal / eIF2-alpha phosphatase phosphorylation constitutive repressor / Protein phosphatase 1, regulatory subunit 15A/B, C-terminal / : / Phosphatase-1 catalytic subunit binding region / : / EIF2B subunit epsilon LbH domain / Translation initiation factor IF2/IF5 domain / Translation initiation factor IF2/IF5, N-terminal / Translation initiation factor IF2/IF5, zinc-binding ...Protein phosphatase 1, regulatory subunit 15B, N-terminal / eIF2-alpha phosphatase phosphorylation constitutive repressor / Protein phosphatase 1, regulatory subunit 15A/B, C-terminal / : / Phosphatase-1 catalytic subunit binding region / : / EIF2B subunit epsilon LbH domain / Translation initiation factor IF2/IF5 domain / Translation initiation factor IF2/IF5, N-terminal / Translation initiation factor IF2/IF5, zinc-binding / Translation initiation factor IF2/IF5 / Domain found in IF2B/IF5 / domain present in translation initiation factor eIF2B and eIF5 / Initiation factor eIF2 gamma, C-terminal / Initiation factor eIF2 gamma, domain 2 / Initiation factor eIF2 gamma, GTP-binding domain / Initiation factor eIF2 gamma, C terminal / Translation initiation factor 2, alpha subunit / Translation initiation factor 2, alpha subunit, middle domain superfamily / Translation initiation factor 2, alpha subunit, C-terminal / IF2a, S1-like domain / Eukaryotic translation initiation factor 2 alpha subunit / : / Nucleotidyl transferase domain / Nucleotidyl transferase / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / S1 domain profile. / Translation elongation factor EFTu-like, domain 2 / Elongation factor Tu domain 2 / Ribosomal protein S1-like RNA-binding domain / S1 RNA binding domain / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / S1 domain / Nucleotide-diphospho-sugar transferases / Translation protein, beta-barrel domain superfamily / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Eukaryotic translation initiation factor 2 subunit 1 / Eukaryotic translation initiation factor 2 subunit 2 / Eukaryotic translation initiation factor 2 subunit 3 / Protein phosphatase 1 regulatory subunit 15B / Translation initiation factor eIF2B subunit gamma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsDe Miguel, C. / Thorkelsson, S.R. / Wang, C. / Bertolotti, A.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MC_U105185860 United Kingdom
Wellcome Trust206367/Z/ 17/Z United Kingdom
CitationJournal: Science / Year: 2025
Title: Termination of the integrated stress response.
Authors: Claudia De Miguel / Sigurdur R Thorkelsson / Agnieszka Fatalska / George Hodgson / Chao Wang / Anne Bertolotti /
Abstract: Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by ...Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.
History
DepositionDec 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 19, 2025Provider: repository / Type: Initial release
Revision 1.1Nov 26, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Translation initiation factor eIF-2B subunit gamma
A: Protein phosphatase 1 regulatory subunit 15B
C: Eukaryotic translation initiation factor 2 subunit 2
D: Eukaryotic translation initiation factor 2 subunit 3
B: Eukaryotic translation initiation factor 2 subunit 1


Theoretical massNumber of molelcules
Total (without water)188,0265
Polymers188,0265
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Translation initiation factor eIF-2B subunit gamma / eIF-2B GDP-GTP exchange factor subunit gamma


Mass: 50304.230 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: Q9NR50
#2: Protein Protein phosphatase 1 regulatory subunit 15B


Mass: 11927.307 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: Expi293 / Gene: PPP1R15B / Plasmid: PXJ41 / Cell line (production host): Expi293 / Production host: Homo sapiens (human) / References: UniProt: Q5SWA1
#3: Protein Eukaryotic translation initiation factor 2 subunit 2 / Eukaryotic translation initiation factor 2 subunit beta / eIF-2-beta


Mass: 38454.484 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P20042
#4: Protein Eukaryotic translation initiation factor 2 subunit 3 / Eukaryotic translation initiation factor 2 subunit gamma X / eIF-2gX


Mass: 51178.406 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P41091, protein-synthesizing GTPase
#5: Protein Eukaryotic translation initiation factor 2 subunit 1 / Eukaryotic translation initiation factor 2 subunit alpha / eIF-2alpha


Mass: 36161.180 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Expi293 / References: UniProt: P05198
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Local refinement of P-eIF2-eIF2B complex bound to R15B focused on an eIF2Bg and an eIF2g subunits.
Type: COMPLEX
Details: FLAG-R15B was expressed in Expi293 human cells and it immunopurified with a native P-eIF2-eIF2B complex.
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human) / Cellular location: cytoplasm
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293 / Plasmid: PXJ41
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2100 mMpotassium chlorideKCl1
31 mMtris(2-carboxyethyl)phosphineTCEP1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 75000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 9438

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Processing

EM software
IDNameVersionCategory
2EPUimage acquisition
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
13PHENIX1.21.2_5419:model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 167091 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingSource name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038350
ELECTRON MICROSCOPYf_angle_d0.73111289
ELECTRON MICROSCOPYf_dihedral_angle_d5.2081149
ELECTRON MICROSCOPYf_chiral_restr0.0481324
ELECTRON MICROSCOPYf_plane_restr0.0041454

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