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- PDB-7oni: Structure of Neddylated CUL5 C-terminal region-RBX2-ARIH2* -

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Basic information

Entry
Database: PDB / ID: 7oni
TitleStructure of Neddylated CUL5 C-terminal region-RBX2-ARIH2*
Components
  • Cullin-5
  • E3 ubiquitin-protein ligase ARIH2
  • NEDD8
  • RING-box protein 2
KeywordsLIGASE / CUL5 / NEDD8 / UBQ / UBIQUITIN / ARIH2 / RBX2
Function / homology
Function and homology information


developmental cell growth / RBR-type E3 ubiquitin transferase / ERBB2 signaling pathway / NEDD8 transferase activity / regulation of proteolysis / protein neddylation / ubiquitin conjugating enzyme binding / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process ...developmental cell growth / RBR-type E3 ubiquitin transferase / ERBB2 signaling pathway / NEDD8 transferase activity / regulation of proteolysis / protein neddylation / ubiquitin conjugating enzyme binding / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / response to redox state / positive regulation of protein targeting to mitochondrion / SCF ubiquitin ligase complex / hematopoietic stem cell proliferation / TGF-beta receptor signaling activates SMADs / protein K63-linked ubiquitination / site of DNA damage / cullin family protein binding / anatomical structure morphogenesis / protein K48-linked ubiquitination / ubiquitin ligase complex / post-translational protein modification / intrinsic apoptotic signaling pathway / Iron uptake and transport / Vif-mediated degradation of APOBEC3G / G1/S transition of mitotic cell cycle / protein modification process / modification-dependent protein catabolic process / calcium channel activity / protein localization / Inactivation of CSF3 (G-CSF) signaling / protein tag activity / Downregulation of ERBB2 signaling / protein polyubiquitination / ubiquitin-protein transferase activity / UCH proteinases / ubiquitin protein ligase activity / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / Cargo recognition for clathrin-mediated endocytosis / signaling receptor activity / Neddylation / ubiquitin-dependent protein catabolic process / protein ubiquitination / copper ion binding / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / proteolysis / extracellular exosome / zinc ion binding / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
E3 ubiquitin-protein ligase ARIH2 / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / Nedd8-like ubiquitin / IBR domain, a half RING-finger domain / IBR domain / In Between Ring fingers / TRIAD supradomain / TRIAD supradomain profile. ...E3 ubiquitin-protein ligase ARIH2 / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / Nedd8-like ubiquitin / IBR domain, a half RING-finger domain / IBR domain / In Between Ring fingers / TRIAD supradomain / TRIAD supradomain profile. / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Cullin / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Cullin / 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. / Ring finger / Ubiquitin conserved site / Ubiquitin domain / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin domain signature. / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase ARIH2 / NEDD8 / Cullin-5 / RING-box protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsKostrhon, S.P. / prabu, J.R. / Schulman, B.A.
Funding support Germany, 3items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)H2020 789016-NEDD8Activate Germany
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Nat Chem Biol / Year: 2021
Title: CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation.
Authors: Sebastian Kostrhon / J Rajan Prabu / Kheewoong Baek / Daniel Horn-Ghetko / Susanne von Gronau / Maren Klügel / Jérôme Basquin / Arno F Alpi / Brenda A Schulman /
Abstract: An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to ...An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.
History
DepositionMay 25, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / em_admin / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Oct 6, 2021Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
C: Cullin-5
H: E3 ubiquitin-protein ligase ARIH2
R: RING-box protein 2
N: NEDD8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,07911
Polymers170,6214
Non-polymers4587
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-5 / / CUL-5 / Vasopressin-activated calcium-mobilizing receptor 1 / VACM-1


Mass: 91085.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL5, VACM1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q93034
#2: Protein E3 ubiquitin-protein ligase ARIH2 / ARI-2 / Protein ariadne-2 homolog / RING-type E3 ubiquitin transferase ARIH2 / Triad1 protein


Mass: 57879.820 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: mutations : L381A E382A E455A / Source: (gene. exp.) Homo sapiens (human) / Gene: ARIH2, ARI2, TRIAD1, HT005
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: O95376, RBR-type E3 ubiquitin transferase
#3: Protein RING-box protein 2 / Rbx2 / CKII beta-binding protein 1 / CKBBP1 / RING finger protein 7 / Regulator of cullins 2 / ...Rbx2 / CKII beta-binding protein 1 / CKBBP1 / RING finger protein 7 / Regulator of cullins 2 / Sensitive to apoptosis gene protein


Mass: 12425.073 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RNF7, RBX2, ROC2, SAG / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UBF6
#4: 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: 9230.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NEDD8
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q15843
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Zn
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: Neddylated CUL5 C-terminal region-RBX2-ARIH2 / Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding 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
Image recordingElectron dose: 14.9 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM softwareName: RELION / Version: 3.1.1 / Category: final Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 191792 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039065
ELECTRON MICROSCOPYf_angle_d0.50712275
ELECTRON MICROSCOPYf_dihedral_angle_d3.8361230
ELECTRON MICROSCOPYf_chiral_restr0.0381391
ELECTRON MICROSCOPYf_plane_restr0.0031571

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