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- PDB-8tqo: Eukaryotic translation initiation factor 2B tetramer -

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Basic information

Entry
Database: PDB / ID: 8tqo
TitleEukaryotic translation initiation factor 2B tetramer
Components
  • Translation initiation factor eIF-2B subunit beta
  • Translation initiation factor eIF-2B subunit delta
  • Translation initiation factor eIF-2B subunit epsilon
  • Translation initiation factor eIF-2B subunit gamma
KeywordsTRANSLATION / Protein translation / eIF2B / integrated stress response
Function / homology
Function and homology information


eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / oligodendrocyte development / guanyl-nucleotide exchange factor complex / astrocyte development / astrocyte differentiation / regulation of translational initiation / positive regulation of translational initiation / response to glucose ...eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / oligodendrocyte development / guanyl-nucleotide exchange factor complex / astrocyte development / astrocyte differentiation / regulation of translational initiation / positive regulation of translational initiation / response to glucose / ovarian follicle development / translation initiation factor binding / translational initiation / translation initiation factor activity / myelination / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / response to peptide hormone / regulation of translation / T cell receptor signaling pathway / response to heat / positive regulation of apoptotic process / GTP binding / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / W2 domain / W2 domain profile. / Nucleotidyl transferase domain ...Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / Initiation factor 2B-related / Initiation factor 2B-like, C-terminal / Initiation factor 2 subunit family / eIF4-gamma/eIF5/eIF2-epsilon / Domain at the C-termini of GCD6, eIF-2B epsilon, eIF-4 gamma and eIF-5 / W2 domain / W2 domain profile. / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / Trimeric LpxA-like superfamily / Nucleotide-diphospho-sugar transferases / Armadillo-type fold
Similarity search - Domain/homology
Translation initiation factor eIF2B subunit beta / Translation initiation factor eIF2B subunit epsilon / Translation initiation factor eIF2B subunit gamma / Translation initiation factor eIF2B subunit delta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsWang, L. / Lawrence, R. / Sangwan, S. / Anand, A. / Shoemaker, S. / Deal, A. / Marqusee, S. / Watler, P.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1K99GM143527 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM050945 United States
CitationJournal: Nat Chem Biol / Year: 2024
Title: A helical fulcrum in eIF2B coordinates allosteric regulation of stress signaling.
Authors: Rosalie E Lawrence / Sophie R Shoemaker / Aniliese Deal / Smriti Sangwan / Aditya A Anand / Lan Wang / Susan Marqusee / Peter Walter /
Abstract: The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation ...The integrated stress response (ISR) enables cells to survive a variety of acute stresses, but chronic activation of the ISR underlies age-related diseases. ISR signaling downregulates translation and activates expression of stress-responsive factors that promote return to homeostasis and is initiated by inhibition of the decameric guanine nucleotide exchange factor eIF2B. Conformational and assembly transitions regulate eIF2B activity, but the allosteric mechanisms controlling these dynamic transitions and mediating the therapeutic effects of the small-molecule ISR inhibitor ISRIB are unknown. Using hydrogen-deuterium exchange-mass spectrometry and cryo-electron microscopy, we identified a central α-helix whose orientation allosterically coordinates eIF2B conformation and assembly. Biochemical and cellular signaling assays show that this 'switch-helix' controls eIF2B activity and signaling. In sum, the switch-helix acts as a fulcrum of eIF2B conformational regulation and is a highly conserved actuator of ISR signal transduction. This work uncovers a conserved allosteric mechanism and unlocks new therapeutic possibilities for ISR-linked diseases.
History
DepositionAug 8, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Translation initiation factor eIF-2B subunit epsilon
I: Translation initiation factor eIF-2B subunit gamma
D: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit delta


Theoretical massNumber of molelcules
Total (without water)229,4064
Polymers229,4064
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 80452.586 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B5, EIF2BE / Production host: Escherichia coli (E. coli) / References: UniProt: Q13144
#2: 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B3 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NR50
#3: Protein Translation initiation factor eIF-2B subunit beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 41008.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B2, EIF2BB / Production host: Escherichia coli (E. coli) / References: UniProt: P49770
#4: Protein Translation initiation factor eIF-2B subunit delta / eIF-2B GDP-GTP exchange factor subunit delta


Mass: 57640.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B4, EIF2BD / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UI10

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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: Translation initiation factor 2B decamer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.53 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 45.8 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 72000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00211323
ELECTRON MICROSCOPYf_angle_d0.50915364
ELECTRON MICROSCOPYf_dihedral_angle_d3.7071552
ELECTRON MICROSCOPYf_chiral_restr0.0431822
ELECTRON MICROSCOPYf_plane_restr0.0051963

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