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- PDB-7b5s: Ubiquitin ligation to F-box protein substrates by SCF-RBR E3-E3 s... -

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Entry
Database: PDB / ID: 7b5s
TitleUbiquitin ligation to F-box protein substrates by SCF-RBR E3-E3 super-assembly: CUL1-RBX1-ARIH1 Ariadne. Transition State 1
Components
  • Cullin-1
  • E3 ubiquitin-protein ligase ARIH1
  • E3 ubiquitin-protein ligase RBX1
KeywordsLIGASE / ubiquitin / ubiquitin ligase / E3 ligase / F-box protein / RBR ligase / Cullin-RING-Ligase / CRL / SCF / NEDD8 / Post-translational modification / ubiquitylation
Function / homology
Function and homology information


ISG15 ligase activity / PKR/eIFalpha signaling / ubiquitin-like protein transferase activity / RBR-type E3 ubiquitin transferase / Parkin-FBXW7-Cul1 ubiquitin ligase complex / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy ...ISG15 ligase activity / PKR/eIFalpha signaling / ubiquitin-like protein transferase activity / RBR-type E3 ubiquitin transferase / Parkin-FBXW7-Cul1 ubiquitin ligase complex / negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy / regulation of xenophagy / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Cul7-RING ubiquitin ligase complex / regulation of cell cycle process / neural crest cell differentiation / RNA polymerase II transcription initiation surveillance / Modulation of host responses by IFN-stimulated genes / positive regulation of protein autoubiquitination / protein neddylation / ubiquitin conjugating enzyme binding / regulation of BMP signaling pathway / NEDD8 ligase activity / regulation of mitophagy / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / VCB complex / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / regulation of TOR signaling / Cul2-RING ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / SCF ubiquitin ligase complex / regulation of mitotic cytokinesis / regulation of DNA damage checkpoint / negative regulation of type I interferon production / Cul3-RING ubiquitin ligase complex / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / RSV-host interactions / Prolactin receptor signaling / regulation of cell cycle phase transition / Cul4-RING E3 ubiquitin ligase complex / Lewy body / regulation of stem cell population maintenance / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / limb development / protein monoubiquitination / cullin family protein binding / Cajal body / centrosome duplication / regulation of DNA-templated DNA replication initiation / cilium assembly / intrinsic apoptotic signaling pathway / ribosome-associated ubiquitin-dependent protein catabolic process / signal transduction in response to DNA damage / ubiquitin ligase complex / negative regulation of insulin receptor signaling pathway / Nuclear events stimulated by ALK signaling in cancer / regulation of cellular response to insulin stimulus / protein K48-linked ubiquitination / transcription-coupled nucleotide-excision repair / post-translational protein modification / positive regulation of TORC1 signaling / regulation of embryonic development / replication fork processing / cellular response to amino acid stimulus / regulation of mitotic cell cycle / negative regulation of canonical NF-kappaB signal transduction / site of DNA damage / Regulation of BACH1 activity / T cell activation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / epigenetic regulation of gene expression / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Dectin-1 mediated noncanonical NF-kB signaling / Degradation of DVL / Degradation of CRY and PER proteins / nucleotide-excision repair / regulation of autophagy / Iron uptake and transport / Activation of NF-kappaB in B cells / Degradation of GLI1 by the proteasome / Recognition of DNA damage by PCNA-containing replication complex / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / RING-type E3 ubiquitin transferase / PKR-mediated signaling / Hedgehog 'on' state / Vif-mediated degradation of APOBEC3G
Similarity search - Function
: / E3 ubiquitin-protein ligase ARIH1, UBA-like domain / Cullin Repeats / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / 5 helical Cullin repeat like / IBR domain, a half RING-finger domain / IBR domain / IBR domain ...: / E3 ubiquitin-protein ligase ARIH1, UBA-like domain / Cullin Repeats / Ariadne domain / Ariadne domain / E3 ubiquitin ligase RBR family / 5 helical Cullin repeat like / IBR domain, a half RING-finger domain / IBR 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, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin alpha solenoid domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / Zinc finger, C3HC4 RING-type / Zinc finger, C3HC4 type (RING finger) / Ring finger / Winged helix-like DNA-binding domain superfamily/Winged helix DNA-binding domain / Zinc finger RING-type profile. / Zinc finger, RING-type / Arc Repressor Mutant, subunit A / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / Cullin-1 / E3 ubiquitin-protein ligase ARIH1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsHorn-Ghetko, D. / Prabu, J.R. / Schulman, B.A.
Funding support Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)H2020 789016-NEDD8Activate Germany
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Nature / Year: 2021
Title: Ubiquitin ligation to F-box protein targets by SCF-RBR E3-E3 super-assembly.
Authors: Daniel Horn-Ghetko / David T Krist / J Rajan Prabu / Kheewoong Baek / Monique P C Mulder / Maren Klügel / Daniel C Scott / Huib Ovaa / Gary Kleiger / Brenda A Schulman /
Abstract: E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates. However, rather ...E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates. However, rather than functioning individually, many neddylated cullin-RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family-which together account for nearly half of all ubiquitin ligases in humans-form E3-E3 super-assemblies. Here, by studying CRLs in the SKP1-CUL1-F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3-E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3-E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3-E3 super-assembly may therefore underlie widespread ubiquitylation.
History
DepositionDec 7, 2020Deposition site: PDBE / Processing site: PDBE
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Assembly

Deposited unit
C: Cullin-1
H: E3 ubiquitin-protein ligase ARIH1
R: E3 ubiquitin-protein ligase RBX1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)166,6158
Polymers166,2883
Non-polymers3275
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5520 Å2
ΔGint-24 kcal/mol
Surface area49900 Å2
MethodPISA

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Components

#1: Protein Cullin-1 / CUL-1


Mass: 89800.367 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q13616
#2: Protein E3 ubiquitin-protein ligase ARIH1 / H7-AP2 / HHARI / Monocyte protein 6 / MOP-6 / Protein ariadne-1 homolog / ARI-1 / UbcH7-binding ...H7-AP2 / HHARI / Monocyte protein 6 / MOP-6 / Protein ariadne-1 homolog / ARI-1 / UbcH7-binding protein / UbcM4-interacting protein / Ubiquitin-conjugating enzyme E2-binding protein 1


Mass: 64197.777 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARIH1, ARI, MOP6, UBCH7BP, HUSSY-27 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9Y4X5, RBR-type E3 ubiquitin transferase
#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: Trichoplusia ni (cabbage looper)
References: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Zn
Has ligand of interestN
Has protein modificationN

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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

Component
IDNameTypeEntity IDParent-IDSource
1NEDD8-CUL1-RBX1-SKP1-SKP2-CKSHS1-Cyclin A-CDK2-p27-UBE2L3~Ub~ARIH1. Transition State 1 composite map.COMPLEX#1-#30MULTIPLE SOURCES
2Cullin-1, E3 ubiquitin-protein ligase RBX1COMPLEX#1, #31RECOMBINANT
3E3 ubiquitin-protein ligase ARIH1COMPLEX#21RECOMBINANT
Molecular weightValue: 0.30 MDa
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
23Escherichia coli (E. coli)562
32Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.8
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 FIELD
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 623409 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067820
ELECTRON MICROSCOPYf_angle_d0.71410542
ELECTRON MICROSCOPYf_dihedral_angle_d9.5391021
ELECTRON MICROSCOPYf_chiral_restr0.0441142
ELECTRON MICROSCOPYf_plane_restr0.0051342

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