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- PDB-7f66: eIF2B-SFSV NSs-1-eIF2 -

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Basic information

Entry
Database: PDB / ID: 7f66
TitleeIF2B-SFSV NSs-1-eIF2
Components
  • (Eukaryotic translation initiation factor 2 subunit ...) x 2
  • (Translation initiation factor eIF-2B subunit ...) x 5
  • Non-structural protein NS-S
  • eIF2beta
KeywordsTRANSLATION / translation initiation factor / viral protein
Function / homology
Function and homology information


regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / methionyl-initiator methionine tRNA binding / eukaryotic translation initiation factor 2B complex / negative regulation of translational initiation in response to stress ...regulation of translation in response to endoplasmic reticulum stress / translation initiation ternary complex / glial limiting end-foot / response to kainic acid / Cellular response to mitochondrial stress / response to manganese-induced endoplasmic reticulum stress / positive regulation of type B pancreatic cell apoptotic process / methionyl-initiator methionine tRNA binding / eukaryotic translation initiation factor 2B complex / negative regulation of translational initiation in response to stress / Response of EIF2AK1 (HRI) to heme deficiency / Recycling of eIF2:GDP / PERK-mediated unfolded protein response / PERK regulates gene expression / eukaryotic translation initiation factor 2 complex / regulation of translational initiation in response to stress / selenocysteine metabolic process / selenocysteine incorporation / protein-synthesizing GTPase / cytoplasmic translational initiation / translation factor activity, RNA binding / oligodendrocyte development / selenocysteine insertion sequence binding / formation of translation preinitiation complex / guanyl-nucleotide exchange factor complex / astrocyte development / eukaryotic 48S preinitiation complex / astrocyte differentiation / Formation of the ternary complex, and subsequently, the 43S complex / regulation of translational initiation / Translation initiation complex formation / Ribosomal scanning and start codon recognition / Response of EIF2AK4 (GCN2) to amino acid deficiency / L13a-mediated translational silencing of Ceruloplasmin expression / GTP hydrolysis and joining of the 60S ribosomal subunit / positive regulation of translational initiation / response to glucose / stress granule assembly / ovarian follicle development / translation initiation factor binding / translational initiation / translation initiation factor activity / cellular response to amino acid starvation / myelination / response to endoplasmic reticulum stress / guanyl-nucleotide exchange factor activity / central nervous system development / hippocampus development / ABC-family proteins mediated transport / PKR-mediated signaling / response to peptide hormone / cytoplasmic stress granule / cellular response to UV / ribosome binding / regulation of translation / T cell receptor signaling pathway / cellular response to heat / cellular response to oxidative stress / response to heat / cadherin binding / positive regulation of apoptotic process / GTPase activity / synapse / GTP binding / RNA binding / extracellular exosome / ATP binding / membrane / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Phlebovirus, non structural protein / Rift valley fever virus non structural protein-like / Rift valley fever virus non structural protein (NSs) like / 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 ...Phlebovirus, non structural protein / Rift valley fever virus non structural protein-like / Rift valley fever virus non structural protein (NSs) like / 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. / IF2a, S1-like domain / Translation initiation factor 2, alpha subunit / Translation initiation factor 2, alpha subunit, middle domain superfamily / Translation initiation factor 2, alpha subunit, C-terminal / Eukaryotic translation initiation factor 2 alpha subunit / Initiation factor eIF2 gamma, domain 2 / Initiation factor eIF2 gamma, GTP-binding domain / Initiation factor eIF2 gamma, C-terminal / Initiation factor eIF2 gamma, C terminal / Nucleotidyl transferase domain / Nucleotidyl transferase / NagB/RpiA transferase-like / Translation elongation factor EF1A/initiation factor IF2gamma, C-terminal / Trimeric LpxA-like superfamily / 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 / S1 domain / Translational (tr)-type GTP-binding domain / Elongation factor Tu GTP binding domain / Translational (tr)-type guanine nucleotide-binding (G) domain profile. / Nucleotide-diphospho-sugar transferases / Armadillo-type fold / 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 / Non-structural protein NS-S / Eukaryotic translation initiation factor 2 subunit 3 / 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)
Sandfly fever sicilian virus
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsKashiwagi, K. / Ito, T.
Funding support Japan, 3items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP19H03172 Japan
Japan Agency for Medical Research and Development (AMED)JP21gm1410001 Japan
Japan Society for the Promotion of Science (JSPS)JP18K14644 Japan
CitationJournal: Nat Commun / Year: 2021
Title: eIF2B-capturing viral protein NSs suppresses the integrated stress response.
Authors: Kazuhiro Kashiwagi / Yuichi Shichino / Tatsuya Osaki / Ayako Sakamoto / Madoka Nishimoto / Mari Takahashi / Mari Mito / Friedemann Weber / Yoshiho Ikeuchi / Shintaro Iwasaki / Takuhiro Ito /
Abstract: Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated ...Various stressors such as viral infection lead to the suppression of cap-dependent translation and the activation of the integrated stress response (ISR), since the stress-induced phosphorylated eukaryotic translation initiation factor 2 [eIF2(αP)] tightly binds to eIF2B to prevent it from exchanging guanine nucleotide molecules on its substrate, unphosphorylated eIF2. Sandfly fever Sicilian virus (SFSV) evades this cap-dependent translation suppression through the interaction between its nonstructural protein NSs and host eIF2B. However, its precise mechanism has remained unclear. Here, our cryo-electron microscopy (cryo-EM) analysis reveals that SFSV NSs binds to the α-subunit of eIF2B in a competitive manner with eIF2(αP). Together with SFSV NSs, eIF2B retains nucleotide exchange activity even in the presence of eIF2(αP), in line with the cryo-EM structures of the eIF2B•SFSV NSs•unphosphorylated eIF2 complex. A genome-wide ribosome profiling analysis clarified that SFSV NSs expressed in cultured human cells attenuates the ISR triggered by thapsigargin, an endoplasmic reticulum stress inducer. Furthermore, SFSV NSs introduced in rat hippocampal neurons and human induced-pluripotent stem (iPS) cell-derived motor neurons exhibits neuroprotective effects against the ISR-inducing stress. Since ISR inhibition is beneficial in various neurological disease models, SFSV NSs may be a promising therapeutic ISR inhibitor.
History
DepositionJun 24, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 1, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Assembly

Deposited unit
A: Translation initiation factor eIF-2B subunit alpha
B: Translation initiation factor eIF-2B subunit alpha
C: Translation initiation factor eIF-2B subunit beta
D: Translation initiation factor eIF-2B subunit beta
E: Translation initiation factor eIF-2B subunit gamma
F: Translation initiation factor eIF-2B subunit gamma
G: Translation initiation factor eIF-2B subunit delta
H: Translation initiation factor eIF-2B subunit delta
I: Translation initiation factor eIF-2B subunit epsilon
J: Translation initiation factor eIF-2B subunit epsilon
K: Non-structural protein NS-S
L: Non-structural protein NS-S
N: Eukaryotic translation initiation factor 2 subunit 1
O: eIF2beta
S: Eukaryotic translation initiation factor 2 subunit 3


Theoretical massNumber of molelcules
Total (without water)670,65815
Polymers670,65815
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

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


Mass: 33908.316 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
#2: Protein Translation initiation factor eIF-2B subunit beta / S20I15 / S20III15 / eIF-2B GDP-GTP exchange factor subunit beta


Mass: 39039.547 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
#3: Protein Translation initiation factor eIF-2B subunit gamma / eIF2Bg / 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
#4: 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
#5: 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

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Eukaryotic translation initiation factor 2 subunit ... , 2 types, 2 molecules NS

#7: 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S1, EIF2A / Production host: Homo sapiens (human) / References: UniProt: P05198
#9: 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 genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EIF2S3, EIF2G / Production host: Homo sapiens (human) / References: UniProt: P41091, protein-synthesizing GTPase

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Protein / Protein/peptide , 2 types, 3 molecules KLO

#6: Protein Non-structural protein NS-S


Mass: 29695.385 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sandfly fever sicilian virus / Gene: NSS / Production host: Escherichia coli (E. coli) / References: UniProt: P12792
#8: Protein/peptide eIF2beta


Mass: 1209.482 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)

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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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of eIF2B, eIF2, and SFSV NSsCOMPLEXall0MULTIPLE SOURCES
2eIF2B, eIF2COMPLEX#1-#5, #7-#91RECOMBINANT
3SFSV NSsCOMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Sandfly fever sicilian virus28292
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Escherichia coli (E. coli)562
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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114377 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00234314
ELECTRON MICROSCOPYf_angle_d0.52846592
ELECTRON MICROSCOPYf_dihedral_angle_d12.56112109
ELECTRON MICROSCOPYf_chiral_restr0.0445505
ELECTRON MICROSCOPYf_plane_restr0.0046023

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