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- EMDB-27033: Cryo-EM structure of human APOBEC3G/HIV-1 Vif/CBFbeta/ELOB/ELOC d... -

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Entry
Database: EMDB / ID: EMD-27033
TitleCryo-EM structure of human APOBEC3G/HIV-1 Vif/CBFbeta/ELOB/ELOC dimeric complex in State 1
Map data
Sample
  • Complex: HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with human APOBEC3G and RNA
    • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3G
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • RNA: RNA (5'-R(P*UP*AP*AP*AP*UP*AP*UP*U)-3')
    • RNA: RNA (5'-R(P*AP*AP*AP*AP*UP*AP*UP*U)-3')
  • Ligand: ZINC ION
KeywordsViral protein / RNA binding protein / Complex / Ubiquitin E3 ligase / VIRAL PROTEIN-IMMUNE SYSTEM-RNA complex
Function / homology
Function and homology information


RUNX3 regulates RUNX1-mediated transcription / apolipoprotein B mRNA editing enzyme complex / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / dCTP deaminase activity / 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 ...RUNX3 regulates RUNX1-mediated transcription / apolipoprotein B mRNA editing enzyme complex / RUNX1 regulates transcription of genes involved in BCR signaling / RUNX1 regulates transcription of genes involved in interleukin signaling / dCTP deaminase activity / 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 / cytidine deamination / base conversion or substitution editing / single-stranded DNA cytosine deaminase / negative regulation of CD4-positive, alpha-beta T cell differentiation / DNA cytosine deamination / lymphocyte differentiation / cytidine to uridine editing / cytidine deaminase activity / negative regulation of viral process / RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs) / negative regulation of single stranded viral RNA replication via double stranded DNA intermediate / RUNX2 regulates genes involved in cell migration / RUNX2 regulates genes involved in differentiation of myeloid cells / Transcriptional regulation by RUNX2 / transposable element silencing / RUNX1 regulates transcription of genes involved in differentiation of keratinocytes / myeloid cell differentiation / target-directed miRNA degradation / RUNX3 Regulates Immune Response and Cell Migration / elongin complex / VCB complex / definitive hemopoiesis / RUNX1 regulates transcription of genes involved in differentiation of myeloid cells / Regulation of RUNX1 Expression and Activity / Cul5-RING ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / negative regulation of viral genome replication / 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 / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / APOBEC3G mediated resistance to HIV-1 infection / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RUNX3 regulates p14-ARF / 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 / positive regulation of defense response to virus by host / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / cell maturation / RNA Polymerase II Pre-transcription Events / viral life cycle / transcription corepressor binding / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / virion component / Vif-mediated degradation of APOBEC3G / P-body / Regulation of RUNX3 expression and activity / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / Transcriptional regulation of granulopoiesis / protein polyubiquitination / osteoblast differentiation / Regulation of RUNX2 expression and activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / defense response to virus / Estrogen-dependent gene expression / sequence-specific DNA binding / host cell cytoplasm / transcription by RNA polymerase II / transcription coactivator activity / protein ubiquitination / ribonucleoprotein complex / innate immune response / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / host cell plasma membrane / negative regulation of transcription by RNA polymerase II / positive regulation of transcription by RNA polymerase II / RNA binding / zinc ion binding / nucleoplasm / identical protein binding / membrane / nucleus
Similarity search - Function
Retroviral Vif (Viral infectivity) protein / Retroviral Vif (Viral infectivity) protein / Core-binding factor, beta subunit / Core-binding factor, beta subunit superfamily / Core binding factor beta subunit / Novel AID APOBEC clade 2 / : / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain ...Retroviral Vif (Viral infectivity) protein / Retroviral Vif (Viral infectivity) protein / Core-binding factor, beta subunit / Core-binding factor, beta subunit superfamily / Core binding factor beta subunit / Novel AID APOBEC clade 2 / : / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain / Cytidine and deoxycytidylate deaminases domain profile. / Elongin B / Elongin-C / Cytidine deaminase-like / 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 / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
Core-binding factor subunit beta / Elongin-C / Elongin-B / Virion infectivity factor / DNA dC->dU-editing enzyme APOBEC-3G
Similarity search - Component
Biological speciesHomo sapiens (human) / Human immunodeficiency virus 1 / Spodoptera frugiperda (fall armyworm)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLi Y / Langley C / Azumaya CM / Echeverria I / Chesarino NM / Emerman M / Cheng Y / Gross JD
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI150476 United States
CitationJournal: Nature / Year: 2023
Title: The structural basis for HIV-1 Vif antagonism of human APOBEC3G.
Authors: Yen-Li Li / Caroline A Langley / Caleigh M Azumaya / Ignacia Echeverria / Nicholas M Chesarino / Michael Emerman / Yifan Cheng / John D Gross /
Abstract: The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles. ...The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles. The lentiviruses encode a protein, Vif, that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this 'molecular arms race' plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBEC3G (A3G) bound to HIV-1 Vif, and the hijacked cellular proteins that promote ubiquitin-mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find that RNA is a molecular glue for the Vif-A3G interaction, enabling Vif to repress A3G by ubiquitin-dependent and -independent mechanisms. Our results suggest a model in which Vif antagonizes A3G by intercepting it in its most dangerous form for the virus-when bound to RNA and on the pathway to packaging-to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism by which RNA binding helps to position key residues necessary for viral antagonism of a host antiviral gene.
History
DepositionMay 19, 2022-
Header (metadata) releaseFeb 15, 2023-
Map releaseFeb 15, 2023-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27033.png

Downloads & links

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Map

FileDownload / File: emd_27033.map.gz / Format: CCP4 / Size: 166.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 352 pix.
= 293.92 Å		0.84 Å/pix.
x 352 pix.
= 293.92 Å		0.84 Å/pix.
x 352 pix.
= 293.92 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.007
Minimum - Maximum-0.01567156 - 0.041168228
Average (Standard dev.)0.00005224664 (±0.0012629061)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 293.91998 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Composite map made by focused refinement of the...

Fileemd_27033_additional_1.map
AnnotationComposite map made by focused refinement of the second A3G-VCBC with weaker density
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Additional map: Sharpened primary map by DeepEMhancer

Fileemd_27033_additional_2.map
AnnotationSharpened primary map by DeepEMhancer
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Additional map: sharpened composite map by DeepEMhancer

Fileemd_27033_additional_3.map
Annotationsharpened composite map by DeepEMhancer
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Additional map: Density modified primary map

Fileemd_27033_additional_4.map
AnnotationDensity modified primary map
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Additional map: Density modified composite map

Fileemd_27033_additional_5.map
AnnotationDensity modified composite map
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Half map: #2

Fileemd_27033_half_map_1.map
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Half map: #1

Fileemd_27033_half_map_2.map
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Sample components

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Entire : HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with hum...

EntireName: HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with human APOBEC3G and RNA
Components
  • Complex: HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with human APOBEC3G and RNA
    • Protein or peptide: DNA dC->dU-editing enzyme APOBEC-3G
    • Protein or peptide: Virion infectivity factor
    • Protein or peptide: Core-binding factor subunit beta
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • RNA: RNA (5'-R(P*UP*AP*AP*AP*UP*AP*UP*U)-3')
    • RNA: RNA (5'-R(P*AP*AP*AP*AP*UP*AP*UP*U)-3')
  • Ligand: ZINC ION

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Supramolecule #1: HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with hum...

SupramoleculeName: HIV-1 Vif-E3 ligase substrate receptor (VCBC) in complex with human APOBEC3G and RNA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: DNA dC->dU-editing enzyme APOBEC-3G

MacromoleculeName: DNA dC->dU-editing enzyme APOBEC-3G / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: single-stranded DNA cytosine deaminase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.034598 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKPHFRNTVE RMYRDTFSYN FYNRPILSRR NTVWLCYEVK TKGPSRPPLD AKIFRGQVYS ELKYHPEMRF FHWFSKWRKL HRDQEYEVT WYISWSPCTK CTRDMATFLA EDPKVTLTIF VARLYYFWDP DYQEALRSLC QKRDGPRATM KIMNYDEFQH C WSKFVYSQ ...String:
MKPHFRNTVE RMYRDTFSYN FYNRPILSRR NTVWLCYEVK TKGPSRPPLD AKIFRGQVYS ELKYHPEMRF FHWFSKWRKL HRDQEYEVT WYISWSPCTK CTRDMATFLA EDPKVTLTIF VARLYYFWDP DYQEALRSLC QKRDGPRATM KIMNYDEFQH C WSKFVYSQ RELFEPWNNL PKYYILLHIM LGEILRHSMD PPTFTFNFNN EPWVRGRHET YLCYEVERMH NDTWVLLNQR RG FLCNQAP HKHGFLEGRH AELCFLDVIP FWKLDLDQDY RVTCFTSWSP CFSCAQEMAK FISKNKHVSL CIFTARIYDD QGR CQEGLR TLAEAGAKIS IMTYSEFKHC WDTFVDHQGC PFQPWDGLDE HSQDLSGRLR AILQNQENGS SLEGGGGWSH PQFE KGGGS GGGSGGGSWS HPQFEK

UniProtKB: DNA dC->dU-editing enzyme APOBEC-3G

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Macromolecule #2: Virion infectivity factor

MacromoleculeName: Virion infectivity factor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Human immunodeficiency virus 1
Molecular weightTheoretical: 22.556002 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MENRWQVMIV WQVDRMRIRT WKSLVKHHMY VSGKARGWFY RHHYESPHPR ISSEVHIPLG DARLVITTYW GLHTGERDWH LGQGVSIEW RKKRYSTQVD PELADQLIHL YYFDCFSDSA IRKALLGHIV SPRCEYQAGH NKVGSLQYLA LAALITPKKI K PPLPSVTK ...String:
MENRWQVMIV WQVDRMRIRT WKSLVKHHMY VSGKARGWFY RHHYESPHPR ISSEVHIPLG DARLVITTYW GLHTGERDWH LGQGVSIEW RKKRYSTQVD PELADQLIHL YYFDCFSDSA IRKALLGHIV SPRCEYQAGH NKVGSLQYLA LAALITPKKI K PPLPSVTK LTEDRWNKPQ KTKGHRGSHT MNGH

UniProtKB: Virion infectivity factor

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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: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.542188 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MPRVVPDQRS KFENEEFFRK LSRECEIKYT GFRDRPHEER QARFQNACRD GRSEIAFVAT GTNLSLQFFP ASWQGEQRQT PSREYVDLE REAGKVYLKA PMILNGVCVI WKGWIDLQRL DGMGCLEFDE ERAQQEDALA QQAFEEARRR TREFEDRDRS H REEMEVRV SQLLAVTGKK TTRP

UniProtKB: Core-binding factor subunit beta

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Macromolecule #4: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.147781 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMKPQDSG SSANEQAVQ

UniProtKB: Elongin-B

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Macromolecule #5: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 5 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.485135 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MDGEEKTYGG CEGPDAMYVK LISSDGHEFI VKREHALTSG TIKAMLSGPG QFAENETNEV NFREIPSHVL SKVCMYFTYK VRYTNSSTE IPEFPIAPEI ALELLMAANF LDC

UniProtKB: Elongin-C

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Macromolecule #6: RNA (5'-R(P*UP*AP*AP*AP*UP*AP*UP*U)-3')

MacromoleculeName: RNA (5'-R(P*UP*AP*AP*AP*UP*AP*UP*U)-3') / type: rna / ID: 6 / Number of copies: 1
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 2.496529 KDa
SequenceString:
UAAAUAUU

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Macromolecule #7: RNA (5'-R(P*AP*AP*AP*AP*UP*AP*UP*U)-3')

MacromoleculeName: RNA (5'-R(P*AP*AP*AP*AP*UP*AP*UP*U)-3') / type: rna / ID: 7 / Number of copies: 1
Source (natural)Organism: Spodoptera frugiperda (fall armyworm)
Molecular weightTheoretical: 2.519569 KDa
SequenceString:
AAAAUAUU

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Macromolecule #8: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 8 / Number of copies: 6 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

Concentration0.46 mg/mL
BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 57207
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.0)
Final 3D classificationSoftware - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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