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- PDB-6w66: The structure of the F64A, S172A mutant Keap1-BTB domain in compl... -

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Basic information

Entry
Database: PDB / ID: 6w66
TitleThe structure of the F64A, S172A mutant Keap1-BTB domain in complex with SKP1-FBXL17
Components
  • F-box/LRR-repeat protein 17
  • Kelch-like ECH-associated protein 1
  • S-phase kinase-associated protein 1
KeywordsLIGASE/SIGNALING PROTEIN / E3 Ligase / Complex / BTB domain / LIGASE / LIGASE-SIGNALING PROTEIN complex
Function / homology
Function and homology information


synaptic assembly at neuromuscular junction / F-box domain binding / PcG protein complex / regulation of smoothened signaling pathway / 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 ...synaptic assembly at neuromuscular junction / F-box domain binding / PcG protein complex / regulation of smoothened signaling pathway / 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 / 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 / protein ubiquitination / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / negative regulation of DNA-templated transcription / centrosome / regulation of DNA-templated transcription / chromatin / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / nucleoplasm / identical protein binding
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 / Potassium Channel Kv1.1; Chain A / Potassium Channel Kv1.1; Chain A / Kelch / Kelch motif / Kelch repeat type 1 / Leucine Rich repeat / 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
S-phase kinase-associated protein 1 / Kelch-like ECH-associated protein 1 / F-box/LRR-repeat protein 17
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 3.21 Å
AuthorsMena, E.L. / Gee, C.L. / 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 16, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Sep 2, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Oct 28, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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


Theoretical massNumber of molelcules
Total (without water)78,5113
Polymers78,5113
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6450 Å2
ΔGint-43 kcal/mol
Surface area30930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)183.665, 183.665, 55.370
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221
Space group name HallP322"

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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: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): LOBSTR / 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 / Cell line (production host): High Five / 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: 14861.131 Da / Num. of mol.: 1 / Fragment: BTB domain / Mutation: F64A/S172A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): LOBSTR / References: UniProt: Q14145

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.43 Å3/Da / Density % sol: 64.16 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: well solution 37.5 ul of 50 mM MgCl2, 100 mM HEPES pH 7.5, 30% (v/v) PEG MME 550 (E7 Hampton Index) + 12.5ul H2O mixed 1:1 with complex at 15mg/ml in 150 mM NaCl, 25 mM Tris/HCl pH 8.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11583 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 3, 2018
RadiationMonochromator: S111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11583 Å / Relative weight: 1
ReflectionResolution: 3.21→159.06 Å / Num. obs: 17752 / % possible obs: 99.6 % / Redundancy: 10.6 % / Biso Wilson estimate: 101.91 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.289 / Rpim(I) all: 0.093 / Rrim(I) all: 0.304 / Net I/σ(I): 7.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.21-3.4310.24.1453201031390.4521.3444.3630.798
9.07-159.06100.033842584610.0110.03552.599.8

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3.21 Å79.53 Å
Translation3.21 Å79.53 Å

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
Aimless0.7.3data scaling
PHASER2.8.2phasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4CXI, 2ASS, 1FQV

4cxi

2ass

1fqv


Resolution: 3.21→79.53 Å / SU ML: 0.4835 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 37.2992
RfactorNum. reflection% reflection
Rfree0.2896 823 4.7 %
Rwork0.2518 --
obs0.2535 17524 98.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 119.12 Å2
Refinement stepCycle: LAST / Resolution: 3.21→79.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5220 0 0 0 5220
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00165300
X-RAY DIFFRACTIONf_angle_d0.41777155
X-RAY DIFFRACTIONf_chiral_restr0.0385832
X-RAY DIFFRACTIONf_plane_restr0.0026910
X-RAY DIFFRACTIONf_dihedral_angle_d8.3183267
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3.21-3.410.40841160.40552624X-RAY DIFFRACTION93.32
3.41-3.670.38781500.36472765X-RAY DIFFRACTION99.35
3.67-4.040.36641460.29982759X-RAY DIFFRACTION98.71
4.04-4.630.27451200.2482824X-RAY DIFFRACTION99.59
4.63-5.830.28441480.25022809X-RAY DIFFRACTION99.8
5.83-79.50.23241430.19392920X-RAY DIFFRACTION99.84

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