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- PDB-8je2: Cryo-EM structure of neddylated Cul2-Rbx1-EloBC-FEM1B complexed w... -

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Basic information

Entry
Database: PDB / ID: 8je2
TitleCryo-EM structure of neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
Components
  • Cullin-2
  • Elongin-B
  • Elongin-C
  • Folliculin-interacting protein 1
  • Protein fem-1 homolog B
KeywordsLIGASE / Complex / E3 ubiquitin ligase / Cullin
Function / homology
Function and homology information


regulation of ubiquitin-protein transferase activity / epithelial cell maturation involved in prostate gland development / positive regulation of B cell apoptotic process / regulation of pro-B cell differentiation / negative regulation of lysosome organization / branching involved in prostate gland morphogenesis / Amino acids regulate mTORC1 / immature B cell differentiation / ATPase inhibitor activity / regulation of DNA damage checkpoint ...regulation of ubiquitin-protein transferase activity / epithelial cell maturation involved in prostate gland development / positive regulation of B cell apoptotic process / regulation of pro-B cell differentiation / negative regulation of lysosome organization / branching involved in prostate gland morphogenesis / Amino acids regulate mTORC1 / immature B cell differentiation / ATPase inhibitor activity / regulation of DNA damage checkpoint / B cell apoptotic process / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / VCB complex / elongin complex / regulation of extrinsic apoptotic signaling pathway via death domain receptors / death receptor binding / negative regulation of TOR signaling / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin ligase complex scaffold activity / TOR signaling / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / positive regulation of TOR signaling / ubiquitin ligase complex / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / 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 / RNA Polymerase II Pre-transcription Events / positive regulation of TORC1 signaling / intrinsic apoptotic signaling pathway / B cell differentiation / cellular response to starvation / transcription corepressor binding / Vif-mediated degradation of APOBEC3G / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Inactivation of CSF3 (G-CSF) signaling / transcription elongation by RNA polymerase II / positive regulation of protein-containing complex assembly / Evasion by RSV of host interferon responses / enzyme activator activity / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / G1/S transition of mitotic cell cycle / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / protein-folding chaperone binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / proteasome-mediated ubiquitin-dependent protein catabolic process / protein ubiquitination / negative regulation of cell population proliferation / lysosomal membrane / apoptotic process / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / nucleolus / enzyme binding / negative regulation of transcription by RNA polymerase II / mitochondrion / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Cullin protein neddylation domain ...Folliculin-interacting protein family / Folliculin-interacting protein, N-terminal domain / Folliculin-interacting protein, middle domain / Folliculin-interacting protein, C-terminal domain / Folliculin-interacting protein N-terminus / Folliculin-interacting protein middle domain / Folliculin-interacting protein C-terminus / Tripartite DENN domain, FNIP1/2-type / Tripartite DENN FNIP1/2-type domain profile. / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Elongin-C / Elongin B / 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 / Ankyrin repeat / SKP1/BTB/POZ domain superfamily / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing 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
Cullin-2 / Elongin-C / Elongin-B / Folliculin-interacting protein 1 / Protein fem-1 homolog B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.63 Å
AuthorsDai, Z. / Liang, L. / Yin, Y.X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81621063, 31800626 China
CitationJournal: EMBO J / Year: 2024
Title: Structural insights into the ubiquitylation strategy of the oligomeric CRL2 E3 ubiquitin ligase.
Authors: Zonglin Dai / Ling Liang / Weize Wang / Peng Zuo / Shang Yu / Yaqi Liu / Xuyang Zhao / Yishuo Lu / Yan Jin / Fangting Zhang / Dian Ding / Weiwei Deng / Yuxin Yin /
Abstract: Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been ...Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2 in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2 is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2 according to substrates with different scales.
History
DepositionMay 15, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 28, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cullin-2
B: Elongin-B
C: Elongin-C
D: Protein fem-1 homolog B
H: Folliculin-interacting protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)312,9766
Polymers312,9105
Non-polymers651
Water00
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 , 5 types, 5 molecules ABCDH

#1: Protein Cullin-2 / CUL-2


Mass: 87927.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13617
#2: 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: 11748.406 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
#3: 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: 11045.694 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
#4: Protein Protein fem-1 homolog B / FEM1b / FEM1-beta / Fem-1-like death receptor-binding protein alpha / Fem-1-like in apoptotic ...FEM1b / FEM1-beta / Fem-1-like death receptor-binding protein alpha / Fem-1-like in apoptotic pathway protein alpha / F1A-alpha


Mass: 70688.406 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FEM1B, F1AA, KIAA0396 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9UK73
#5: Protein Folliculin-interacting protein 1


Mass: 131499.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FNIP1, KIAA1961 / Production host: Homo sapiens (human) / References: UniProt: Q8TF40

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Non-polymers , 1 types, 1 molecules

#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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: Neddylated Cul2-Rbx1-EloBC-FEM1B complexed with FNIP1-FLCN
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 1.93 mg/ml / Embedding 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: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.63 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 433719 / Symmetry type: POINT

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