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- EMDB-40919: The cryo-EM structure of PPP2R5A/HIV-1 Vif/CBFb/EloB/EloC complex -

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Basic information

Entry
Database: EMDB / ID: EMD-40919
TitleThe cryo-EM structure of PPP2R5A/HIV-1 Vif/CBFb/EloB/EloC complex
Map data
Sample
  • Complex: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform
KeywordsHIV Vif / Cul5 E3 ligase / PPP2R5A / VIRAL PROTEIN
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 / RUNX2 regulates osteoblast differentiation / protein phosphatase activator activity / 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 / viral life cycle / Resolution of Sister Chromatid Cohesion / RNA Polymerase II Pre-transcription Events / protein dephosphorylation / transcription corepressor binding / virion component / transcription elongation by RNA polymerase II / RHO GTPases Activate Formins / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Vif-mediated degradation of APOBEC3G / RAF activation / Regulation of RUNX3 expression and activity / 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 / Transcriptional regulation of granulopoiesis / osteoblast differentiation / protein polyubiquitination / Negative regulation of MAPK pathway / 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 (NEW YORK-5 ISOLATE)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.58 Å
AuthorsHu Y / Xiong Y
Funding support United States, 1 items
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, 2023-
Header (metadata) releaseJun 5, 2024-
Map releaseJun 5, 2024-
UpdateJun 5, 2024-
Current statusJun 5, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40919.png

Downloads & links

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Map

FileDownload / File: emd_40919.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-0.0016312819 - 2.0388997
Average (Standard dev.)0.0019068767 (±0.03346807)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 220.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40919_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40919_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC

EntireName: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC
Components
  • Complex: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform

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Supramolecule #1: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC

SupramoleculeName: PPP2R5A in complex with HIV-1 Vif/CBFb/EloB/EloC / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.147781 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMKPQDSG SSANEQAVQ

UniProtKB: Elongin-B

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Macromolecule #2: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.84342 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFLDC

UniProtKB: Elongin-C

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Macromolecule #3: Core-binding factor subunit beta

MacromoleculeName: Core-binding factor subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.644197 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SQDPMPRVVP DQRSKFENEE FFRKLSRECE IKYTGFRDRP HEERQARFQN ACRDGRSEIA FVATGTNLSL QFFPASWQG EQRQTPSREY VDLEREAGKV YLKAPMILNG VCVIWKGWID LQRLDGMGCL EFDEERAQQE DALAQQAFEE A RRRTREFE ...String:
MGSSHHHHHH SQDPMPRVVP DQRSKFENEE FFRKLSRECE IKYTGFRDRP HEERQARFQN ACRDGRSEIA FVATGTNLSL QFFPASWQG EQRQTPSREY VDLEREAGKV YLKAPMILNG VCVIWKGWID LQRLDGMGCL EFDEERAQQE DALAQQAFEE A RRRTREFE DRDRSHREEM EARRQQDPSP GSNLGGGDDL KLR

UniProtKB: Core-binding factor subunit beta

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Macromolecule #4: Virion infectivity factor

MacromoleculeName: Virion infectivity factor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
Molecular weightTheoretical: 20.98224 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MENRWQVMIV WQVDRMRINT WKRLVKHHMY ISRKAKDWFY RHHYESTNPK ISSEVHIPLG DAKLVITTYW GLHTGERDWH LGQGVSIEW RKKRYSTQVD PDLADQLIHL HYFDCFSESA IRNTILGRIV SPRCEYQAGH NKVGSLQYLA LAALIKPKQI K PPLPSVRK LTEDRWNK

UniProtKB: Virion infectivity factor

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Macromolecule #5: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit...

MacromoleculeName: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.266555 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSSSSPPAGA ASAAISASEK VDGFTRKSVR KAQRQKRSQG SSQFRSQGSQ AELHPLPQLK DATSNEQQEL FCQKLQQCCI LFDFMDSVS DLKSKEIKRA TLNELVEYVS TNRGVIVESA YSDIVKMISA NIFRTLPPSD NPDFDPEEDE PTLEASWPHI Q LVYEFFLR ...String:
MSSSSPPAGA ASAAISASEK VDGFTRKSVR KAQRQKRSQG SSQFRSQGSQ AELHPLPQLK DATSNEQQEL FCQKLQQCCI LFDFMDSVS DLKSKEIKRA TLNELVEYVS TNRGVIVESA YSDIVKMISA NIFRTLPPSD NPDFDPEEDE PTLEASWPHI Q LVYEFFLR FLESPDFQPS IAKRYIDQKF VQQLLELFDS EDPRERDFLK TVLHRIYGKF LGLRAFIRKQ INNIFLRFIY ET EHFNGVA ELLEILGSII NGFALPLKAE HKQFLMKVLI PMHTAKGLAL FHAQLAYCVV QFLEKDTTLT EPVIRGLLKF WPK TCSQKE VMFLGEIEEI LDVIEPTQFK KIEEPLFKQI SKCVSSSHFQ VAERALYFWN NEYILSLIEE NIDKILPIMF ASLY KISKE HWNPTIVALV YNVLKTLMEM NGKLFDDLTS SYKAERQREK KKELEREELW KKLEELKLKK ALEKQNSAYN MHSIL SNTS AE

UniProtKB: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit alpha isoform

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.58 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 500511
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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