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- EMDB-27759: SPOP W22R Tetrameric Form -

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Basic information

Entry
Database: EMDB / ID: EMD-27759
TitleSPOP W22R Tetrameric Form
Map dataFull map
Sample
  • Complex: SPOP W22R Mutant (tetrameric form)
    • Protein or peptide: Speckle-type POZ protein
KeywordsSPOP / ubiquitination / cullin / ONCOPROTEIN
Function / homology
Function and homology information


molecular function inhibitor activity / Cul3-RING ubiquitin ligase complex / regulation of proteolysis / Hedgehog 'on' state / protein polyubiquitination / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear speck / ubiquitin protein ligase binding / nucleoplasm / identical protein binding ...molecular function inhibitor activity / Cul3-RING ubiquitin ligase complex / regulation of proteolysis / Hedgehog 'on' state / protein polyubiquitination / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear speck / ubiquitin protein ligase binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
Similarity search - Function
SPOP, C-terminal BACK domain / : / BPM/SPOP, BACK domain / MATH domain / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like / BTB/POZ domain / BTB domain profile. ...SPOP, C-terminal BACK domain / : / BPM/SPOP, BACK domain / MATH domain / MATH/TRAF domain / MATH/TRAF domain profile. / meprin and TRAF homology / TRAF-like / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily
Similarity search - Domain/homology
Speckle-type POZ protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.2 Å
AuthorsCuneo MJ / Mittag T / O'Flynn B / Lo YH
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM112846 United States
CitationJournal: Mol Cell / Year: 2023
Title: Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation.
Authors: Matthew J Cuneo / Brian G O'Flynn / Yu-Hua Lo / Nafiseh Sabri / Tanja Mittag /
Abstract: The speckle-type POZ protein (SPOP) functions in the Cullin3-RING ubiquitin ligase (CRL3) as a receptor for the recognition of substrates involved in cell growth, survival, and signaling. SPOP ...The speckle-type POZ protein (SPOP) functions in the Cullin3-RING ubiquitin ligase (CRL3) as a receptor for the recognition of substrates involved in cell growth, survival, and signaling. SPOP mutations have been attributed to the development of many types of cancers, including prostate and endometrial cancers. Prostate cancer mutations localize in the substrate-binding site of the substrate recognition (MATH) domain and reduce or prevent binding. However, most endometrial cancer mutations are dispersed in seemingly inconspicuous solvent-exposed regions of SPOP, offering no clear basis for their cancer-causing and peculiar gain-of-function properties. Herein, we present the first structure of SPOP in its oligomeric form, uncovering several new interfaces important for SPOP self-assembly and normal function. Given that many previously unaccounted-for cancer mutations are localized in these newly identified interfaces, we uncover molecular mechanisms underlying dysregulation of SPOP function, with effects ranging from gross structural changes to enhanced self-association, and heightened stability and activity.
History
DepositionAug 2, 2022-
Header (metadata) releaseJan 18, 2023-
Map releaseJan 18, 2023-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Downloads & links

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Map

FileDownload / File: emd_27759.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFull map
Voxel sizeX=Y=Z: 1.4526 Å
Density
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-0.29437694 - 1.7551929
Average (Standard dev.)0.0018735272 (±0.061297234)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 435.78 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : SPOP W22R Mutant (tetrameric form)

EntireName: SPOP W22R Mutant (tetrameric form)
Components
  • Complex: SPOP W22R Mutant (tetrameric form)
    • Protein or peptide: Speckle-type POZ protein

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Supramolecule #1: SPOP W22R Mutant (tetrameric form)

SupramoleculeName: SPOP W22R Mutant (tetrameric form) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Speckle-type POZ protein

MacromoleculeName: Speckle-type POZ protein / type: protein_or_peptide / ID: 1 / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.023148 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SRVPSPPPPA EMSSGPVAES RCYTQIKVVK FSYMWTINNF SFCREEMGEV IKSSTFSSGA NDKLKWCLRV NPKGLDEESK DYLSLYLLL VSCPKSEVRA KFKFSILNAK GEETKAMESQ RAYRFVQGKD WGFKKFIRRD FLLDEANGLL PDDKLTLFCE V SVVQDSVN ...String:
SRVPSPPPPA EMSSGPVAES RCYTQIKVVK FSYMWTINNF SFCREEMGEV IKSSTFSSGA NDKLKWCLRV NPKGLDEESK DYLSLYLLL VSCPKSEVRA KFKFSILNAK GEETKAMESQ RAYRFVQGKD WGFKKFIRRD FLLDEANGLL PDDKLTLFCE V SVVQDSVN ISGQNTMNMV KVPECRLADE LGGLWENSRF TDCCLCVAGQ EFQAHKAILA ARSPVFSAMF EHEMEESKKN RV EINDVEP EVFKEMMCFI YTGKAPNLDK MADDLLAAAD KYALERLKVM CEDALCSNLS VENAAEILIL ADLHSADQLK TQA VDFINY HASDVLETSG WKSMVVSHPH LVAEAYRSLA SAQCPFLGPP RKRLKQS

UniProtKB: Speckle-type POZ protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

Concentration1 mg/mL
BufferpH: 7.5 / Details: 20 mM HEPES pH 7.5, 400 mM NaCl, 5 mM DTT
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK III

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 69.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.6 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

3hqi

Final reconstructionResolution.type: BY AUTHOR / Resolution: 6.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 121000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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Atomic model buiding 1

Initial modelPDB ID:

3hqi


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: OTHER
Output model

PDB-8dwt:
SPOP W22R Form 2

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