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- PDB-8dwv: Full-length wild type SPOP -

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ID or keywords:

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Basic information

Entry
Database: PDB / ID: 8dwv
TitleFull-length wild type SPOP
ComponentsSpeckle-type POZ protein
KeywordsONCOPROTEIN / SPOP / ubiquitination / cullin
Function / homology
Function and homology information


regulation of proteolysis / Cul3-RING ubiquitin ligase complex / molecular function inhibitor activity / localization / Hedgehog 'on' state / protein polyubiquitination / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear speck / ubiquitin protein ligase binding / nucleoplasm ...regulation of proteolysis / Cul3-RING ubiquitin ligase complex / molecular function inhibitor activity / localization / Hedgehog 'on' state / protein polyubiquitination / proteasome-mediated ubiquitin-dependent protein catabolic process / nuclear speck / ubiquitin protein ligase binding / nucleoplasm / nucleus / cytoplasm
Similarity search - Function
SPOP, C-terminal 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsCuneo, M.J. / Mittag, T. / O'Flynn, B. / Lo, Y.H.
Funding support United States, 1items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Speckle-type POZ protein
B: Speckle-type POZ protein
E: Speckle-type POZ protein
F: Speckle-type POZ protein
G: Speckle-type POZ protein
H: Speckle-type POZ protein


Theoretical massNumber of molelcules
Total (without water)252,5786
Polymers252,5786
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: SAXS
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Speckle-type POZ protein / HIB homolog 1 / Roadkill homolog 1


Mass: 42096.277 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPOP / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: O43791

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: SPOP E47K Mutant / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 7.5 / Details: 20 mM HEPES pH 7.5, 400 mM NaCl, 5 mM DTT
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 65 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameCategory
7Cootmodel fitting
8UCSF ChimeraXmodel fitting
10PHENIXmodel refinement
14cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 572000 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL
Atomic model buildingPDB-ID: 3HQI

3hqi

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