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- PDB-7trj: The eukaryotic translation initiation factor 2B from Homo sapiens... -

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Basic information

Entry
Database: PDB / ID: 7trj
TitleThe eukaryotic translation initiation factor 2B from Homo sapiens with a H160D mutation in the beta subunit
Components
  • Translation initiation factor eIF-2B subunit alpha
  • 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 / integrated stress response
Function / homology
Function and homology information


eukaryotic translation initiation factor 2B complex / Recycling of eIF2:GDP / cytoplasmic translational initiation / guanyl-nucleotide exchange factor complex / astrocyte development / astrocyte differentiation / oligodendrocyte development / 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 / guanyl-nucleotide exchange factor complex / astrocyte development / astrocyte differentiation / oligodendrocyte development / regulation of translational initiation / positive regulation of translational initiation / response to glucose / ovarian follicle development / translation initiation factor binding / translation initiation factor activity / myelination / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / translational initiation / response to peptide hormone / T cell receptor signaling pathway / regulation of translation / response to heat / positive regulation of apoptotic process / GTP binding / ATP binding / identical protein binding / nucleus / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Translation initiation factor eIF-2B, N-terminal domain / Translation initiation factor eif-2b; domain 2 / Translation initiation factor eIF-2B subunit alpha, N-terminal / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / : / EIF2B subunit epsilon LbH domain ...Translation initiation factor eIF-2B, N-terminal domain / Translation initiation factor eif-2b; domain 2 / Translation initiation factor eIF-2B subunit alpha, N-terminal / : / Translation initiation factor eIF-2B subunit epsilon, N-terminal / Translation initiation factor eIF-2B subunit epsilon, W2 domain / : / : / : / EIF2B subunit epsilon LbH 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 / Four Helix Bundle (Hemerythrin (Met), subunit A) / Armadillo-type fold / Up-down Bundle / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Translation initiation factor eIF2B subunit beta / Translation initiation factor eIF2B subunit epsilon / Translation initiation factor eIF2B subunit alpha / 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: 2.8 Å
AuthorsWang, L. / Schoof, M. / Lawrence, R. / Boone, M. / Frost, A. / Walter, P.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Elife / Year: 2022
Title: A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation.
Authors: Morgane Boone / Lan Wang / Rosalie E Lawrence / Adam Frost / Peter Walter / Michael Schoof /
Abstract: In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic ...In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Previously we showed that translational control is primarily exerted through a conformational switch in eIF2's nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2 (Schoof et al. 2021). Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B's β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed A/I-State model of allosteric ISR regulation.
History
DepositionJan 29, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 21, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Translation initiation factor eIF-2B subunit epsilon
D: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit delta
G: Translation initiation factor eIF-2B subunit alpha
I: Translation initiation factor eIF-2B subunit gamma
B: Translation initiation factor eIF-2B subunit epsilon
C: Translation initiation factor eIF-2B subunit beta
F: Translation initiation factor eIF-2B subunit delta
H: Translation initiation factor eIF-2B subunit alpha
J: Translation initiation factor eIF-2B subunit gamma


Theoretical massNumber of molelcules
Total (without water)522,36310
Polymers522,36310
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
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: 80466.609 Da / Num. of mol.: 2
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 beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 39016.492 Da / Num. of mol.: 2 / Mutation: H160D
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
#3: Protein Translation initiation factor eIF-2B subunit delta / eIF-2B GDP-GTP exchange factor subunit delta


Mass: 57640.168 Da / Num. of mol.: 2
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
#4: Protein Translation initiation factor eIF-2B subunit alpha / eIF-2B GDP-GTP exchange factor subunit alpha


Mass: 33754.148 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232
#5: Protein Translation initiation factor eIF-2B subunit gamma / eIF-2B GDP-GTP exchange factor subunit gamma


Mass: 50304.230 Da / Num. of mol.: 2
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

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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 eIF-2B decamer / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.5 MDa / Experimental value: NO
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: 2 nm / Nominal defocus min: 0.6 nm
Image recordingElectron dose: 67 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.17.1_3660refinement
PHENIX1.17.1_3660refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 170244 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 100.54 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003225654
ELECTRON MICROSCOPYf_angle_d0.82934772
ELECTRON MICROSCOPYf_chiral_restr0.05034104
ELECTRON MICROSCOPYf_plane_restr0.00474414
ELECTRON MICROSCOPYf_dihedral_angle_d19.5373488

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