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- PDB-7kmf: Sugar phosphate activation of the stress sensor eIF2B -

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Basic information

Entry
Database: PDB / ID: 7kmf
TitleSugar phosphate activation of the stress sensor eIF2B
Components(Translation initiation factor eIF-2B subunit ...) x 5
KeywordsTRANSLATION / Translation initiation factor eif-2b
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 / translation initiation factor binding / ovarian follicle development / translational initiation / myelination / translation initiation factor activity / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / response to peptide hormone / regulation of translation / response to heat / T cell receptor signaling pathway / positive regulation of apoptotic process / GTP binding / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
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 / 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. ...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 / 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
6-O-phosphono-beta-D-fructofuranose / 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: 2.91 Å
AuthorsNocek, B. / Hao, Q. / Wong, Y. / Stoll, V. / Sidrauski, C.
CitationJournal: Nat Commun / Year: 2021
Title: Sugar phosphate activation of the stress sensor eIF2B.
Authors: Qi Hao / Jin-Mi Heo / Boguslaw P Nocek / Kevin G Hicks / Vincent S Stoll / Clint Remarcik / Sean Hackett / Lauren LeBon / Rinku Jain / Dan Eaton / Jared Rutter / Yao Liang Wong / Carmela Sidrauski /
Abstract: The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. ...The multi-subunit translation initiation factor eIF2B is a control node for protein synthesis. eIF2B activity is canonically modulated through stress-responsive phosphorylation of its substrate eIF2. The eIF2B regulatory subcomplex is evolutionarily related to sugar-metabolizing enzymes, but the biological relevance of this relationship was unknown. To identify natural ligands that might regulate eIF2B, we conduct unbiased binding- and activity-based screens followed by structural studies. We find that sugar phosphates occupy the ancestral catalytic site in the eIF2Bα subunit, promote eIF2B holoenzyme formation and enhance enzymatic activity towards eIF2. A mutant in the eIF2Bα ligand pocket that causes Vanishing White Matter disease fails to engage and is not stimulated by sugar phosphates. These data underscore the importance of allosteric metabolite modulation for proper eIF2B function. We propose that eIF2B evolved to couple nutrient status via sugar phosphate sensing with the rate of protein synthesis, one of the most energetically costly cellular processes.
History
DepositionNov 2, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)540,54712
Polymers540,02710
Non-polymers5202
Water32418
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Translation initiation factor eIF-2B subunit ... , 5 types, 10 molecules CDFEHGBIJK

#1: Protein Translation initiation factor eIF-2B subunit beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 41049.633 Da / Num. of mol.: 2
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
#2: 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
#3: Protein Translation initiation factor eIF-2B subunit alpha / eIF-2B GDP-GTP exchange factor subunit alpha


Mass: 40552.938 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: F6P / Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2B1, EIF2BA / Production host: Escherichia coli (E. coli) / References: UniProt: Q14232
#4: 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
#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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Sugars / Non-polymers , 2 types, 20 molecules

#6: Sugar ChemComp-F6P / 6-O-phosphono-beta-D-fructofuranose / FRUCTOSE-6-PHOSPHATE / 6-O-phosphono-beta-D-fructose / 6-O-phosphono-D-fructose / 6-O-phosphono-fructose / Fructose 6-phosphate


Type: D-saccharide, beta linking / Mass: 260.136 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C6H13O9P / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
b-D-Fruf6PO3IUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 18 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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: Tranlation initiation factor eif-2B / Type: COMPLEX / Entity ID: #1-#2, #5-#6 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
Details: Prior to grid preparation, the protein mixture was diluted with 25 mM HEPES, 100 mM KCl, 2 mM 446 MgCl2, 1 mM DTT, pH 7.5 to
SpecimenConc.: 0.32 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: eif2a was mixed with eif2bcde in 1.5 :1 molar ratio and incubated on ice.
VitrificationCryogen name: ETHANE

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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: OTHER
Image recordingElectron dose: 44.33 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 6073

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Processing

Software
NameVersionClassification
phenix.real_space_refinedev_3916refinement
PHENIXdev_3916refinement
EM software
IDNameVersionCategory
7Cootmodel fitting
9cryoSPARC2.15initial Euler assignment
10cryoSPARC2.15final Euler assignment
12cryoSPARC2.153D reconstruction
13PHENIXdev_3916model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 2.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 73704 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Details: Real space refinement
Atomic model buildingPDB-ID: 6CAJ

6caj

RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 103.98 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.009123262
ELECTRON MICROSCOPYf_angle_d1.03831600
ELECTRON MICROSCOPYf_chiral_restr0.0643790
ELECTRON MICROSCOPYf_plane_restr0.00734011
ELECTRON MICROSCOPYf_dihedral_angle_d19.59913215

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