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- EMDB-70883: SPOP double donut locally refined MATH domains -

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Basic information

Entry
Database: EMDB / ID: EMD-70883
TitleSPOP double donut locally refined MATH domains
Map datasharpened map
Sample
  • Complex: SPOP double donut locally-refined MATH domains
    • Protein or peptide: Speckle-type POZ protein
Keywordsubiquitination / protein degradation / protein oligomer / substrate adapter / PROTEIN BINDING
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: 3.2 Å
AuthorsCuneo MJ
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: bioRxiv / Year: 2025
Title: The equilibrium between two quaternary assembly states determines the activity of SPOP and its cancer mutants.
Authors: Matthew J Cuneo / Ömer Güllülü / Mohamed-Raafet Ammar / Xinrui Gui / Kelly Churion / Martin Turk / Brian G O'Flynn / Nafiseh Sabri / Tanja Mittag
Abstract: Proteostasis is critical for preventing oncogenesis. Both activating and inactivating mutations in the ubiquitin ligase subunit SPOP result in oncogenesis in different tissues. SPOP assembles into ...Proteostasis is critical for preventing oncogenesis. Both activating and inactivating mutations in the ubiquitin ligase subunit SPOP result in oncogenesis in different tissues. SPOP assembles into filaments that are multivalent for substrates, and substrates have multiple weak motifs for SPOP that are not activated via post-translational modifications. It is thus unclear how regulation is achieved. Here, we show that SPOP filaments circularize into rings that dimerize into up to 2.5 MDa-large, auto-inhibited double donuts. The equilibrium between double donuts and linear filaments determines SPOP activity. Activating and deactivating cancer mutations shift the equilibrium towards the filament or the double donut, respectively, and this influences substrate turnover and subcellular localization. This regulatory mechanism requires long filaments that can circularize into rings, likely explaining the presence of multiple weak SPOP-binding motifs in substrates. Activating and deactivating mutations combine to give rise to intermediate activities, suggesting new levers for cancer therapies.
HIGHLIGHTS: SPOP assemblies exist in an equilibrium between circular double donuts and linear filaments.Double donuts occlude access to the substrate binding site and are inactive.Mutations in ...HIGHLIGHTS: SPOP assemblies exist in an equilibrium between circular double donuts and linear filaments.Double donuts occlude access to the substrate binding site and are inactive.Mutations in different cancers shift the equilibrium towards active or inactive states.Regulation through these structural transitions requires large filamentous assemblies.
History
DepositionMay 29, 2025-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70883.png

Downloads & links

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Map

FileDownload / File: emd_70883.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 400 pix.
= 422.8 Å		1.06 Å/pix.
x 400 pix.
= 422.8 Å		1.06 Å/pix.
x 400 pix.
= 422.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.057 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.521
Minimum - Maximum-4.8272696 - 4.7082276
Average (Standard dev.)-0.0004038736 (±0.044292267)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 422.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_70883_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_70883_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : SPOP double donut locally-refined MATH domains

EntireName: SPOP double donut locally-refined MATH domains
Components
  • Complex: SPOP double donut locally-refined MATH domains
    • Protein or peptide: Speckle-type POZ protein

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Supramolecule #1: SPOP double donut locally-refined MATH domains

SupramoleculeName: SPOP double donut locally-refined MATH domains / 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: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.096277 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSRVPSPPPP AEMSSGPVAE SWCYTQIKVV KFSYMWTINN FSFCREEMGE VIKSSTFSSG ANDKLKWCLR VNPKGLDEES KDYLSLYLL LVSCPKSEVR AKFKFSILNA KGEETKAMES QRAYRFVQGK DWGFKKFIRR DFLLDEANGL LPDDKLTLFC E VSVVQDSV ...String:
MSRVPSPPPP AEMSSGPVAE SWCYTQIKVV KFSYMWTINN FSFCREEMGE VIKSSTFSSG ANDKLKWCLR VNPKGLDEES KDYLSLYLL LVSCPKSEVR AKFKFSILNA KGEETKAMES QRAYRFVQGK DWGFKKFIRR DFLLDEANGL LPDDKLTLFC E VSVVQDSV NISGQNTMNM VKVPECRLAD ELGGLWENSR FTDCCLCVAG QEFQAHKAIL AARSPVFSAM FEHEMEESKK NR VEINDVE PEVFKEMMCF IYTGKAPNLD KMADDLLAAA DKYALERLKV MCEDALCSNL SVENAAEILI LADLHSADQL KTQ AVDFIN YHASDVLETS GWKSMVVSHP HLVAEAYRSL ASAQCPFLGP PRKRLKQ

UniProtKB: Speckle-type POZ protein

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 1.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

8dwv

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 391000
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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