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- PDB-7z8b: Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for m... -

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Basic information

Entry
Database: PDB / ID: 7z8b
TitleStructure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation
Components
  • Cullin-7
  • E3 ubiquitin-protein ligase RBX1
  • F-box/WD repeat-containing protein 8
  • S-phase kinase-associated protein 1
KeywordsLIGASE / Cullin-RING Ubiquitin E3 Ligase
Function / homology
Function and homology information


: / 3M complex / spongiotrophoblast layer development / F-box domain binding / anaphase-promoting complex / PcG protein complex / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / XBP1(S) activates chaperone genes / NEDD8 transferase activity ...: / 3M complex / spongiotrophoblast layer development / F-box domain binding / anaphase-promoting complex / PcG protein complex / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / XBP1(S) activates chaperone genes / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / positive regulation of ubiquitin protein ligase activity / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / positive regulation of dendrite morphogenesis / Cul5-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin-ubiquitin ligase activity / labyrinthine layer blood vessel development / Cul4A-RING E3 ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / regulation of mitotic nuclear division / Cul3-RING ubiquitin ligase complex / Prolactin receptor signaling / Golgi organization / protein monoubiquitination / cullin family protein binding / mitotic cytokinesis / ubiquitin-like ligase-substrate adaptor activity / protein K48-linked ubiquitination / epithelial to mesenchymal transition / vasculogenesis / Nuclear events stimulated by ALK signaling in cancer / positive regulation of TORC1 signaling / Regulation of BACH1 activity / T cell activation / post-translational protein modification / MAP3K8 (TPL2)-dependent MAPK1/3 activation / placenta development / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / molecular function activator activity / Vpu mediated degradation of CD4 / Degradation of DVL / Dectin-1 mediated noncanonical NF-kB signaling / Recognition of DNA damage by PCNA-containing replication complex / cellular response to amino acid stimulus / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Negative regulation of NOTCH4 signaling / Iron uptake and transport / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / DNA Damage Recognition in GG-NER / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / negative regulation of canonical Wnt signaling pathway / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / NOTCH1 Intracellular Domain Regulates Transcription / microtubule cytoskeleton organization / Formation of TC-NER Pre-Incision Complex / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / beta-catenin binding / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / FCERI mediated NF-kB activation / Interleukin-1 signaling / protein polyubiquitination / Orc1 removal from chromatin / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of RAS by GAPs / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / cellular response to UV / Cyclin D associated events in G1 / ubiquitin protein ligase activity / KEAP1-NFE2L2 pathway / Regulation of PLK1 Activity at G2/M Transition / MAPK cascade / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation
Similarity search - Function
CPH domain / Mouse development and cellular proliferation protein Cullin-7 / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) / DOC domain profile. / Anaphase-promoting complex, subunit 10 (APC10) / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like domain superfamily / F-box-like ...CPH domain / Mouse development and cellular proliferation protein Cullin-7 / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) / DOC domain profile. / Anaphase-promoting complex, subunit 10 (APC10) / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like domain superfamily / F-box-like / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / F-box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin / Cullin protein, neddylation domain / Cullin protein neddylation domain / 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 / Quinoprotein alcohol dehydrogenase-like superfamily / SKP1/BTB/POZ domain superfamily / Galactose-binding-like domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Ribosomal protein L2, domain 2 / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / Trp-Asp (WD) repeats signature. / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40/YVTN repeat-like-containing domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / S-phase kinase-associated protein 1 / Cullin-7 / F-box/WD repeat-containing protein 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsHopf, L.V.M. / Schulman, B.A.
Funding supportEuropean Union, Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)789016European Union
Max Planck Society Germany
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structure of CRL7 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation.
Authors: Linus V M Hopf / Kheewoong Baek / Maren Klügel / Susanne von Gronau / Yue Xiong / Brenda A Schulman /
Abstract: Most cullin-RING ubiquitin ligases (CRLs) form homologous assemblies between a neddylated cullin-RING catalytic module and a variable substrate-binding receptor (for example, an F-box protein). ...Most cullin-RING ubiquitin ligases (CRLs) form homologous assemblies between a neddylated cullin-RING catalytic module and a variable substrate-binding receptor (for example, an F-box protein). However, the vertebrate-specific CRL7 is of interest because it eludes existing models, yet its constituent cullin CUL7 and F-box protein FBXW8 are essential for development, and CUL7 mutations cause 3M syndrome. In this study, cryo-EM and biochemical analyses reveal the CRL7 assembly. CUL7's exclusivity for FBXW8 among all F-box proteins is explained by its unique F-box-independent binding mode. In CRL7, the RBX1 (also known as ROC1) RING domain is constrained in an orientation incompatible with binding E2~NEDD8 or E2~ubiquitin intermediates. Accordingly, purified recombinant CRL7 lacks auto-neddylation and ubiquitination activities. Instead, our data indicate that CRL7 serves as a substrate receptor linked via SKP1-FBXW8 to a neddylated CUL1-RBX1 catalytic module mediating ubiquitination. The structure reveals a distinctive CRL-CRL partnership, and provides a framework for understanding CUL7 assemblies safeguarding human health.
History
DepositionMar 17, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 5, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Cullin-7
F: F-box/WD repeat-containing protein 8
R: E3 ubiquitin-protein ligase RBX1
S: S-phase kinase-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)290,3597
Polymers290,1634
Non-polymers1963
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Cullin-7 / / CUL-7


Mass: 191564.359 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL7, KIAA0076 / Production host: Homo sapiens (human) / References: UniProt: Q14999
#2: Protein F-box/WD repeat-containing protein 8 / F-box and WD-40 domain-containing protein 8 / F-box only protein 29


Mass: 67628.852 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FBXW8, FBW6, FBW8, FBX29, FBXO29, FBXW6 / Production host: Homo sapiens (human) / References: UniProt: Q8N3Y1
#3: Protein E3 ubiquitin-protein ligase RBX1 / E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / ...E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / Rbx1 / Regulator of cullins 1 / ROC1


Mass: 12289.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Homo sapiens (human)
References: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase
#4: Protein S-phase kinase-associated protein 1 / / Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of Corti ...Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of Corti protein II / OCP-II / RNA polymerase II elongation factor-like protein / SIII / Transcription elongation factor B polypeptide 1-like / p19skp1


Mass: 18679.965 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SKP1, EMC19, OCP2, SKP1A, TCEB1L / Production host: Homo sapiens (human) / References: UniProt: P63208
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
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: Structure of the CUL7-RBX1-FBXW8-SKP1 cullin-RING ligase complex
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 1.7 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 FIELDBright-field microscopy / Nominal defocus max: 2800 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 58.56 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: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 355547 / Symmetry type: POINT

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