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- PDB-8szk: The cryo-EM structure of PPP2R5A/HIV-1 Vif/CBFb/EloB/EloC complex -

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Basic information

Entry
Database: PDB / ID: 8szk
TitleThe cryo-EM structure of PPP2R5A/HIV-1 Vif/CBFb/EloB/EloC complex
Components
  • Core-binding factor subunit beta
  • Elongin-B
  • Elongin-C
  • Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform
  • Virion infectivity factor
KeywordsVIRAL PROTEIN / HIV Vif / Cul5 E3 ligase / PPP2R5A
Function / homology
Function and homology information


negative regulation of lipid kinase activity / RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / RUNX2 regulates bone development / core-binding factor complex / RUNX1 regulates expression of components of tight junctions / positive regulation of CD8-positive, alpha-beta T cell differentiation / RUNX2 regulates chondrocyte maturation / negative regulation of CD4-positive, alpha-beta T cell differentiation ...negative regulation of lipid kinase activity / RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / RUNX2 regulates bone development / core-binding factor complex / RUNX1 regulates expression of components of tight junctions / positive regulation of CD8-positive, alpha-beta T cell differentiation / RUNX2 regulates chondrocyte maturation / negative regulation of CD4-positive, alpha-beta T cell differentiation / protein phosphatase type 2A complex / lymphocyte differentiation / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / RUNX2 regulates genes involved in cell migration / RUNX2 regulates genes involved in differentiation of myeloid cells / protein phosphatase regulator activity / Transcriptional regulation by RUNX2 / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / myeloid cell differentiation / APC truncation mutants have impaired AXIN binding / AXIN missense mutants destabilize the destruction complex / Truncations of AMER1 destabilize the destruction complex / target-directed miRNA degradation / RUNX3 Regulates Immune Response and Cell Migration / elongin complex / VCB complex / Beta-catenin phosphorylation cascade / Signaling by GSK3beta mutants / CTNNB1 S33 mutants aren't phosphorylated / CTNNB1 S37 mutants aren't phosphorylated / CTNNB1 S45 mutants aren't phosphorylated / CTNNB1 T41 mutants aren't phosphorylated / definitive hemopoiesis / M band / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of RUNX1 Expression and Activity / negative regulation of protein localization to plasma membrane / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / CTLA4 inhibitory signaling / Platelet sensitization by LDL / RUNX1 regulates transcription of genes involved in WNT signaling / RUNX1 regulates estrogen receptor mediated transcription / RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known / protein phosphatase activator activity / RUNX2 regulates osteoblast differentiation / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / phosphoprotein phosphatase activity / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / chromosome, centromeric region / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / positive regulation of protein dephosphorylation / cell maturation / Resolution of Sister Chromatid Cohesion / viral life cycle / RNA Polymerase II Pre-transcription Events / protein dephosphorylation / transcription corepressor binding / virion component / RHO GTPases Activate Formins / transcription elongation by RNA polymerase II / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Vif-mediated degradation of APOBEC3G / Regulation of RUNX3 expression and activity / RAF activation / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Degradation of beta-catenin by the destruction complex / PKR-mediated signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / kinase binding / Z disc / osteoblast differentiation / Transcriptional regulation of granulopoiesis / Negative regulation of MAPK pathway / protein polyubiquitination / Separation of Sister Chromatids / Regulation of RUNX2 expression and activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Neddylation / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / ubiquitin-dependent protein catabolic process / protein-containing complex assembly
Similarity search - Function
Retroviral Vif (Viral infectivity) protein / Retroviral Vif (Viral infectivity) protein / Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Core-binding factor, beta subunit / Core-binding factor, beta subunit superfamily / Core binding factor beta subunit / Elongin B / Elongin-C / S-phase kinase-associated protein 1-like ...Retroviral Vif (Viral infectivity) protein / Retroviral Vif (Viral infectivity) protein / Protein phosphatase 2A, regulatory B subunit, B56 / Protein phosphatase 2A regulatory B subunit (B56 family) / Core-binding factor, beta subunit / Core-binding factor, beta subunit superfamily / Core binding factor beta subunit / Elongin B / Elongin-C / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Armadillo-like helical / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Virion infectivity factor / Core-binding factor subunit beta / Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform / Elongin-C / Elongin-B
Similarity search - Component
Biological speciesHomo sapiens (human)
Human immunodeficiency virus type 1
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.58 Å
AuthorsHu, Y. / Xiong, Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI) United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Structural insights into PPP2R5A degradation by HIV-1 Vif.
Authors: Yingxia Hu / Krista A Delviks-Frankenberry / Chunxiang Wu / Fidel Arizaga / Vinay K Pathak / Yong Xiong /
Abstract: HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the ...HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A-E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif-CBFβ-elongin B-elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif-PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host-virus protein interactions could serve as potential targets for HIV-1 therapeutics.
History
DepositionMay 30, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 5, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Elongin-B
B: Elongin-C
C: Core-binding factor subunit beta
G: Virion infectivity factor
D: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform


Theoretical massNumber of molelcules
Total (without water)124,8845
Polymers124,8845
Non-polymers00
Water00
1


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

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Components

#1: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#2: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10843.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#3: Protein Core-binding factor subunit beta / CBF-beta / Polyomavirus enhancer-binding protein 2 beta subunit / PEA2-beta / PEBP2-beta / SL3-3 ...CBF-beta / Polyomavirus enhancer-binding protein 2 beta subunit / PEA2-beta / PEBP2-beta / SL3-3 enhancer factor 1 subunit beta / SL3/AKV core-binding factor beta subunit


Mass: 23644.197 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CBFB / Production host: Escherichia coli (E. coli) / References: UniProt: Q13951
#4: Protein Virion infectivity factor / Vif / SOR protein


Mass: 20982.240 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Gene: vif / Production host: Escherichia coli (E. coli) / References: UniProt: P12504
#5: Protein Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform / PP2A B subunit isoform B'-alpha / PP2A B subunit isoform B56-alpha / PP2A B subunit isoform PR61- ...PP2A B subunit isoform B'-alpha / PP2A B subunit isoform B56-alpha / PP2A B subunit isoform PR61-alpha / PR61alpha / PP2A B subunit isoform R5-alpha


Mass: 56266.555 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPP2R5A / Production host: Escherichia coli (E. coli) / References: UniProt: Q15172

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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: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Human immunodeficiency virus type 1 group M subtype B (isolate NY5)11698
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
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: 800 nm
Image recordingElectron dose: 60 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: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 500511 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0087564
ELECTRON MICROSCOPYf_angle_d1.03910220
ELECTRON MICROSCOPYf_dihedral_angle_d4.635978
ELECTRON MICROSCOPYf_chiral_restr0.0521114
ELECTRON MICROSCOPYf_plane_restr0.0061312

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