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- PDB-8fvi: Human APOBEC3H bound to HIV-1 Vif in complex with CBF-beta, ELOB,... -

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Basic information

Entry
Database: PDB / ID: 8fvi
TitleHuman APOBEC3H bound to HIV-1 Vif in complex with CBF-beta, ELOB, ELOC, and CUL5
Components
  • Core-binding factor subunit beta
  • Cullin 5
  • DNA dC->dU-editing enzyme APOBEC-3H
  • Elongin-B
  • Elongin-C
  • RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
  • RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')
  • Virion infectivity factor
KeywordsANTIVIRAL PROTEIN / virus-host protein complex
Function / homology
Function and homology information


RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / mRNA Editing: C to U Conversion / Formation of the Editosome / 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 ...RUNX3 regulates RUNX1-mediated transcription / RUNX1 regulates transcription of genes involved in BCR signaling / mRNA Editing: C to U Conversion / Formation of the Editosome / 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 / single-stranded DNA cytosine deaminase / negative regulation of CD4-positive, alpha-beta T cell differentiation / DNA cytosine deamination / cytidine to uridine editing / negative regulation by host of viral genome replication / : / lymphocyte differentiation / cytidine deaminase activity / clearance of foreign intracellular DNA / 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 / retrotransposon silencing / cullin-RING ubiquitin ligase complex / 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 / 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 / RUNX3 regulates p14-ARF / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / 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 / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / cell maturation / viral life cycle / RNA Polymerase II Pre-transcription Events / transcription corepressor binding / Evasion by RSV of host interferon responses / virion component / 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 / P-body / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Regulation of expression of SLITs and ROBOs / osteoblast differentiation / protein polyubiquitination / Transcriptional regulation of granulopoiesis / Regulation of RUNX2 expression and activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / protein-macromolecule adaptor activity / Neddylation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / defense response to virus / Estrogen-dependent gene expression / host cell cytoplasm / sequence-specific DNA binding / transcription by RNA polymerase II / transcription coactivator activity / protein ubiquitination / 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 / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
APOBEC3H / APOBEC3 / 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 / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain ...APOBEC3H / APOBEC3 / 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 / APOBEC/CMP deaminase, zinc-binding / Cytidine and deoxycytidylate deaminases zinc-binding region signature. / Cytidine and deoxycytidylate deaminase domain / Cytidine and deoxycytidylate deaminases domain profile. / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cytidine deaminase-like / Cullin protein, neddylation domain / Cullin protein neddylation domain / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / 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 / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
RNA / Cullin 5 / Virion infectivity factor / Core-binding factor subunit beta / Elongin-C / Elongin-B / DNA dC->dU-editing enzyme APOBEC-3H
Similarity search - Component
Biological speciesHomo sapiens (human)
Human immunodeficiency virus 1
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsIto, F. / Alvarez-Cabrera, A.L. / Zhou, Z.H. / Chen, X.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI150524 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
Authors: Fumiaki Ito / Ana L Alvarez-Cabrera / Kyumin Kim / Z Hong Zhou / Xiaojiang S Chen /
Abstract: Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific ...Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific human A3s for proteasomal degradation. Vif recruits cellular transcription cofactor CBF-β and Cullin-5 (CUL5) RING E3 ubiquitin ligase to bind different A3s distinctively, but how this is accomplished remains unclear in the absence of the atomic structure of the complex. Here, we present the cryo-EM structures of HIV-1 Vif in complex with human A3H, CBF-β and components of CUL5 ubiquitin ligase (CUL5, ELOB, and ELOC). Vif nucleates the entire complex by directly binding four human proteins, A3H, CBF-β, CUL5, and ELOC. The structures reveal a large interface area between A3H and Vif, primarily mediated by an α-helical side of A3H and a five-stranded β-sheet of Vif. This A3H-Vif interface unveils the basis for sensitivity-modulating polymorphism of both proteins, including a previously reported gain-of-function mutation in Vif isolated from HIV/AIDS patients. Our structural and functional results provide insights into the remarkable interplay between HIV and humans and would inform development efforts for anti-HIV therapeutics.
History
DepositionJan 19, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 6, 2023Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
0: Core-binding factor subunit beta
1: Virion infectivity factor
A: DNA dC->dU-editing enzyme APOBEC-3H
B: RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')
C: RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')
x: Cullin 5
y: Elongin-B
z: Elongin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,94210
Polymers126,8118
Non-polymers1312
Water181
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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Protein , 6 types, 6 molecules 01Axyz

#1: 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: 18643.814 Da / Num. of mol.: 1 / Fragment: UNP residues 1-157
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
#2: Protein Virion infectivity factor / Vif / SOR protein


Mass: 21160.451 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human immunodeficiency virus 1 / Strain: pNL4-3 / Gene: vif / Production host: Escherichia coli (E. coli) / References: UniProt: P12504
#3: Protein DNA dC->dU-editing enzyme APOBEC-3H / APOBEC-related protein 10 / ARP-10 / Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3H / A3H


Mass: 22103.410 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APOBEC3H / Production host: Escherichia coli (E. coli)
References: UniProt: Q6NTF7, single-stranded DNA cytosine deaminase
#6: Protein Cullin 5 /


Mass: 36613.980 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL5 / Production host: Escherichia coli (E. coli) / References: UniProt: A0A2K5ZN28
#7: 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: 11488.030 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
#8: 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

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RNA chain , 2 types, 2 molecules BC

#4: RNA chain RNA(5'-R(AP*UP*UP*UP*UP*UP*UP*UP*UP*U)-3')


Mass: 3039.740 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Escherichia coli (E. coli)
#5: RNA chain RNA(5'-R(*AP*AP*AP*AP*AP*AP*AP*AP*A)-3')


Mass: 2917.895 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Escherichia coli (E. coli)

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Non-polymers , 2 types, 3 molecules

#9: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#10: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: Hetero-hexameric complex of HIV-1 Vif and human APOBEC3H, CBF-beta, ELOB, ELOC, and CUL5
Type: COMPLEX / Entity ID: #1-#8 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.12 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Human immunodeficiency virus 111676
41Escherichia coli (E. coli)562
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 0.15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELDBright-field microscopy / Nominal magnification: 165000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingAverage exposure time: 3.5 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 14725

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3637921
3D reconstructionResolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 89986 / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.016968
ELECTRON MICROSCOPYf_angle_d0.8269485
ELECTRON MICROSCOPYf_dihedral_angle_d6.5631056
ELECTRON MICROSCOPYf_chiral_restr0.041036
ELECTRON MICROSCOPYf_plane_restr0.0051147

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