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- PDB-8q7h: Structure of CUL9-RBX1 ubiquitin E3 ligase complex in unneddylate... -

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Basic information

Entry
Database: PDB / ID: 8q7h
TitleStructure of CUL9-RBX1 ubiquitin E3 ligase complex in unneddylated and neddylated conformation - focused cullin dimer
Components
  • Cullin-9
  • E3 ubiquitin-protein ligase RBX1
  • NEDD8
  • Unknown
KeywordsLIGASE / Cullin-RING RBR E3 Ligase
Function / homology
Function and homology information


cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / regulation of proteolysis / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / positive regulation of protein autoubiquitination / protein neddylation ...cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / regulation of proteolysis / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / ubiquitin-ubiquitin ligase activity / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Cul4A-RING E3 ubiquitin ligase complex / regulation of mitotic nuclear division / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / Prolactin receptor signaling / TGF-beta receptor signaling activates SMADs / protein monoubiquitination / cullin family protein binding / anatomical structure morphogenesis / protein K48-linked ubiquitination / Nuclear events stimulated by ALK signaling in cancer / positive regulation of TORC1 signaling / post-translational protein modification / regulation of cellular response to insulin stimulus / Regulation of BACH1 activity / T cell activation / cellular response to amino acid stimulus / Degradation of DVL / Iron uptake and transport / Recognition of DNA damage by PCNA-containing replication complex / Degradation of GLI1 by the proteasome / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / DNA Damage Recognition in GG-NER / protein modification process / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / RING-type E3 ubiquitin transferase / negative regulation of canonical Wnt signaling pathway / Degradation of beta-catenin by the destruction complex / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Dual Incision in GG-NER / Evasion by RSV of host interferon responses / NOTCH1 Intracellular Domain Regulates Transcription / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / microtubule cytoskeleton organization / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / Interleukin-1 signaling / Dual incision in TC-NER / modification-dependent protein catabolic process / Gap-filling DNA repair synthesis and ligation in TC-NER / Orc1 removal from chromatin / protein polyubiquitination / Regulation of RAS by GAPs / positive regulation of protein catabolic process / cellular response to UV / Regulation of RUNX2 expression and activity / protein tag activity / UCH proteinases / MAPK cascade / ubiquitin protein ligase activity / KEAP1-NFE2L2 pathway / protein localization / Antigen processing: Ubiquitination & Proteasome degradation / Cargo recognition for clathrin-mediated endocytosis / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / ubiquitin-dependent protein catabolic process / spermatogenesis / positive regulation of canonical NF-kappaB signal transduction / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / molecular adaptor activity / protein ubiquitination / DNA repair / DNA damage response / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / proteolysis / extracellular exosome / zinc ion binding / nucleoplasm / ATP binding / nucleus
Similarity search - Function
: / : / : / CPH domain / Mouse development and cellular proliferation protein Cullin-7 / IBR domain, a half RING-finger domain / Nedd8-like ubiquitin / IBR domain / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) ...: / : / : / CPH domain / Mouse development and cellular proliferation protein Cullin-7 / IBR domain, a half RING-finger domain / Nedd8-like ubiquitin / IBR domain / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) / DOC domain profile. / Anaphase-promoting complex, subunit 10 (APC10) / IBR domain / In Between Ring fingers / TRIAD supradomain / TRIAD supradomain profile. / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / : / Cullin, conserved site / Cullin family signature. / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Galactose-binding-like domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Armadillo-like helical / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ribosomal protein L2, domain 2 / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / NEDD8 / Cullin-9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsHopf, L.V.M. / Horn-Ghetko, D. / 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: 2024
Title: Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex.
Authors: Daniel Horn-Ghetko / Linus V M Hopf / Ishita Tripathi-Giesgen / Jiale Du / Sebastian Kostrhon / D Tung Vu / Viola Beier / Barbara Steigenberger / J Rajan Prabu / Luca Stier / Elias M Bruss / ...Authors: Daniel Horn-Ghetko / Linus V M Hopf / Ishita Tripathi-Giesgen / Jiale Du / Sebastian Kostrhon / D Tung Vu / Viola Beier / Barbara Steigenberger / J Rajan Prabu / Luca Stier / Elias M Bruss / Matthias Mann / Yue Xiong / Brenda A Schulman /
Abstract: Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with ...Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with E2 enzymes to catalyze ubiquitylation. However, the vertebrate-specific CUL9 complex with RBX1 (also called ROC1), of interest due to its tumor suppressive interaction with TP53, uniquely encompasses both cullin-RING and RBR domains. Here, cryo-EM, biochemistry and cellular assays elucidate a 1.8-MDa hexameric human CUL9-RBX1 assembly. Within one dimeric subcomplex, an E2-bound RBR domain is activated by neddylation of its own cullin domain and positioning from the adjacent CUL9-RBX1 in trans. Our data show CUL9 as unique among RBX1-bound cullins in dependence on the metazoan-specific UBE2F neddylation enzyme, while the RBR domain protects it from deneddylation. Substrates are recruited to various upstream domains, while ubiquitylation relies on both CUL9's neddylated cullin and RBR domains achieving self-assembled and chimeric cullin-RING/RBR E3 ligase activity.
History
DepositionAug 16, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jul 31, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cullin-9
B: Cullin-9
C: E3 ubiquitin-protein ligase RBX1
N: NEDD8
E: Unknown
D: E3 ubiquitin-protein ligase RBX1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)610,56216
Polymers609,9076
Non-polymers65410
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Cullin-9 / CUL-9 / UbcH7-associated protein 1 / p53-associated parkin-like cytoplasmic protein


Mass: 281686.062 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL9, H7AP1, KIAA0708, PARC / Production host: Homo sapiens (human) / References: UniProt: Q8IWT3
#2: 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.: 2 / Mutation: p.M1_A4del
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
#3: Protein NEDD8 / Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / ...Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / Ubiquitin-like protein Nedd8


Mass: 9086.562 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q15843
#4: Protein Unknown


Mass: 12868.854 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 10 / 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 CUL9-RBX1 ubiquitin E3 ligase complex in unneddylated and neddylated conformation - focused cullin dimer
Type: COMPLEX / Details: Structure of dimeric subunit / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 3 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: 2800 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.17.1_3660: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 71928 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00418314
ELECTRON MICROSCOPYf_angle_d0.5825195
ELECTRON MICROSCOPYf_dihedral_angle_d4.3132930
ELECTRON MICROSCOPYf_chiral_restr0.0393151
ELECTRON MICROSCOPYf_plane_restr0.0053295

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