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- PDB-6wcq: Structure of a substrate-bound DQC ubiquitin ligase -

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Basic information

Entry
Database: PDB / ID: 6wcq
TitleStructure of a substrate-bound DQC ubiquitin ligase
Components
  • Cullin-1
  • F-box/LRR-repeat protein 17
  • Kelch-like ECH-associated protein 1
  • S-phase kinase-associated protein 1
KeywordsLIGASE / ubiquitin / E3-ligase / multiprotein complex / substrate recognition
Function / homology
Function and homology information


Parkin-FBXW7-Cul1 ubiquitin ligase complex / synaptic assembly at neuromuscular junction / F-box domain binding / PcG protein complex / regulation of smoothened signaling pathway / cullin-RING ubiquitin ligase complex / regulation of xenophagy / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Cul7-RING ubiquitin ligase complex ...Parkin-FBXW7-Cul1 ubiquitin ligase complex / synaptic assembly at neuromuscular junction / F-box domain binding / PcG protein complex / regulation of smoothened signaling pathway / cullin-RING ubiquitin ligase complex / regulation of xenophagy / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Cul7-RING ubiquitin ligase complex / regulation of cell cycle process / neural crest cell differentiation / Nuclear events mediated by NFE2L2 / regulation of BMP signaling pathway / ubiquitin ligase activator activity / regulation of mitophagy / negative regulation of response to oxidative stress / regulation of centrosome duplication / regulation of TOR signaling / SCF ubiquitin ligase complex / Cul3-RING ubiquitin ligase complex / regulation of DNA damage checkpoint / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Prolactin receptor signaling / ubiquitin ligase complex scaffold activity / protein quality control for misfolded or incompletely synthesized proteins / limb development / cullin family protein binding / centrosome duplication / transcription regulator inhibitor activity / cilium assembly / ubiquitin-like ligase-substrate adaptor activity / intrinsic apoptotic signaling pathway / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / inclusion body / molecular function activator activity / regulation of mitotic cell cycle / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / actin filament / G1/S transition of mitotic cell cycle / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Vpu mediated degradation of CD4 / Dectin-1 mediated noncanonical NF-kB signaling / Degradation of CRY and PER proteins / Activation of NF-kappaB in B cells / Iron uptake and transport / Degradation of GLI1 by the proteasome / regulation of autophagy / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Negative regulation of NOTCH4 signaling / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / beta-catenin binding / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / GSK3B-mediated proteasomal degradation of PD-L1(CD274) / NOTCH1 Intracellular Domain Regulates Transcription / regulation of circadian rhythm / Degradation of beta-catenin by the destruction complex / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / CLEC7A (Dectin-1) signaling / SCF(Skp2)-mediated degradation of p27/p21 / FCERI mediated NF-kB activation / protein polyubiquitination / disordered domain specific binding / Interleukin-1 signaling / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / Orc1 removal from chromatin / Cyclin D associated events in G1 / Regulation of RUNX2 expression and activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of PLK1 Activity at G2/M Transition / KEAP1-NFE2L2 pathway / Downstream TCR signaling / nervous system development / Antigen processing: Ubiquitination & Proteasome degradation / regulation of inflammatory response / Neddylation / cellular response to oxidative stress / midbody / heterochromatin formation / ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / regulation of apoptotic process / intracellular iron ion homeostasis / regulation of cell cycle / positive regulation of canonical NF-kappaB signal transduction / protein ubiquitination / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / centrosome / regulation of DNA-templated transcription
Similarity search - Function
: / : / F-box/LRR-repeat protein 15, leucine rich repeat domain / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like / Kelch-like ECH-associated protein 1 / F-box-like domain superfamily ...: / : / F-box/LRR-repeat protein 15, leucine rich repeat domain / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like / Kelch-like ECH-associated protein 1 / F-box-like domain superfamily / : / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / F-box domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / Kelch repeat type 1 / 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 / Leucine Rich repeat / Cullin alpha solenoid domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / Kelch-type beta propeller / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
S-phase kinase-associated protein 1 / Cullin-1 / Kelch-like ECH-associated protein 1 / F-box/LRR-repeat protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 8.5 Å
AuthorsMena, E.L. / Jevtic, P. / Greber, B.J. / Gee, C.L. / Lew, B.G. / Akopian, D. / Nogales, E. / Kuriyan, J. / Rape, M.
Funding support United States, 1items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nature / Year: 2020
Title: Structural basis for dimerization quality control.
Authors: Elijah L Mena / Predrag Jevtić / Basil J Greber / Christine L Gee / Brandon G Lew / David Akopian / Eva Nogales / John Kuriyan / Michael Rape /
Abstract: Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration. Dimerization quality control further improves proteostasis by eliminating complexes of ...Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration. Dimerization quality control further improves proteostasis by eliminating complexes of aberrant composition, but how it detects incorrect subunits remains unknown. Here we provide structural insight into target selection by SCF-FBXL17, a dimerization-quality-control E3 ligase that ubiquitylates and helps to degrade inactive heterodimers of BTB proteins while sparing functional homodimers. We find that SCF-FBXL17 disrupts aberrant BTB dimers that fail to stabilize an intermolecular β-sheet around a highly divergent β-strand of the BTB domain. Complex dissociation allows SCF-FBXL17 to wrap around a single BTB domain, resulting in robust ubiquitylation. SCF-FBXL17 therefore probes both shape and complementarity of BTB domains, a mechanism that is well suited to establish quality control of complex composition for recurrent interaction modules.
History
DepositionMar 31, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2020Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 28, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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  • EMDB-21617
  • Imaged by UCSF Chimera
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Assembly

Deposited unit
A: S-phase kinase-associated protein 1
B: F-box/LRR-repeat protein 17
C: Kelch-like ECH-associated protein 1
D: Cullin-1


Theoretical massNumber of molelcules
Total (without water)183,7504
Polymers183,7504
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area7050 Å2
ΔGint-55 kcal/mol
Surface area50560 Å2

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Components

#1: Protein S-phase kinase-associated protein 1 / SKP1 / Cyclin-A/CDK2-associated protein p19 / p19A / Organ of Corti protein 2 / OCP-2 / Organ of ...SKP1 / 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: Trichoplusia ni (cabbage looper) / References: UniProt: P63208
#2: Protein F-box/LRR-repeat protein 17 / F-box and leucine-rich repeat protein 17 / F-box only protein 13


Mass: 44970.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FBXL17, FBL17, FBX13, FBXO13 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UF56
#3: Protein Kelch-like ECH-associated protein 1 / Cytosolic inhibitor of Nrf2 / INrf2 / Kelch-like protein 19


Mass: 70173.484 Da / Num. of mol.: 1 / Mutation: V99A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q14145
#4: Protein Cullin-1 / CUL-1


Mass: 49926.520 Da / Num. of mol.: 1 / Fragment: residues 1-434
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

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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: CUL1-SKP1-FBXL17-KEAP1 complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solution
IDSpecimen-IDpH
118
228
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
220 mMHEPES-NaOH1
31 mMDTT1
4150 mMSodium chlorideNaCl2
520 mMHEPES-NaOH2
61 mMDTT2
Specimen
IDExperiment-IDEmbedding appliedShadowing appliedStaining appliedVitrification appliedDetails (eV)
11NONONOYESCrosslinked with BS3
21NONONOYESCrosslinked with BS3
Specimen support
IDSpecimen-IDDetails (eV)Grid materialGrid mesh size (divisions/in.)Grid type
11Glow discharge before deposition of graphene oxide.GOLD300Quantifoil, UltrAuFoil, R1.2/1.3
22A thin carbon film was floated onto the grids, which were glow discharged after drying.COPPERQuantifoil R2/2
Vitrification
IDInstrumentCryogen nameHumidity (%)Specimen-IDChamber temperature (K)Entry-ID
1FEI VITROBOT MARK IVETHANE-PROPANE10012776WCQ
2FEI VITROBOT MARK IVETHANE-PROPANE10022776WCQ

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
EM imaging

Accelerating voltage: 200 kV / Alignment procedure: COMA FREE / C2 aperture diameter: 50 µm / Cryogen: NITROGEN / Electron source: FIELD EMISSION GUN / Illumination mode: FLOOD BEAM / Model: FEI TALOS ARCTICA / Mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3000 nm / Specimen holder model: OTHER

IDNominal defocus min (nm)Specimen-ID
120001
215002
Image recording
IDImaging-IDElectron dose (e/Å2)Film or detector modelNum. of grids imagedDetector mode
1160GATAN K3 (6k x 4k)1
2250GATAN K2 SUMMIT (4k x 4k)1SUPER-RESOLUTION

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameVersionCategoryImaging-IDDetails (eV)
2SerialEMimage acquisition1
4CTFFIND4CTF correction
5GctfCTF correction
8UCSF Chimeramodel fittingFIT IN MAP
10SerialEMimage acquisition2
11RELION3initial Euler assignment
12cryoSPARCinitial Euler assignment
13RELION3final Euler assignment
15RELION33D reconstruction
16PHENIXmodel refinementREAL SPACE REFINE
Image processingDetails: Datasets from K3 and K2 were joined for the final reconstruction.
CTF correctionDetails: As implemented in RELION. / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 824561
Details: Total number of particles for both datasets. Selected using RELION auto-picking (Laplacian-of-Gaussian).
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 8.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 160256 / Algorithm: FOURIER SPACE / Num. of class averages: 2 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Details: Coordinates were fitted as rigid bodies or fragments in Chimera and subsequently geometry-optimized using PHENIX real space refinement.
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
11LDK

1ldk

11LDK1PDBexperimental model
21X1X

1x1x

11X1X2PDBexperimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028266
ELECTRON MICROSCOPYf_angle_d0.56211147
ELECTRON MICROSCOPYf_dihedral_angle_d11.8075061
ELECTRON MICROSCOPYf_chiral_restr0.0381273
ELECTRON MICROSCOPYf_plane_restr0.0031423

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