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- EMDB-18171: YPEL5-bound WDR26-CTLH E3 ligase - assembly II -

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Basic information

Entry
Database: EMDB / ID: EMD-18171
TitleYPEL5-bound WDR26-CTLH E3 ligase - assembly II
Map data
Sample
  • Complex: Complex of human WDR26-CTLH E3 ligase bound to YPEL5
KeywordsE3 ubiquitin ligase / CTLH / GID / NMNAT1 / NAD / NADH / YPEL5 / LIGASE
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 11.2 Å
AuthorsChrustowicz J / Sherpa D / Schulman BA
Funding support Germany, European Union, 3 items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)H2020 789016-NEDD8ActivateEuropean Union
German Research Foundation (DFG)SCHU 3196/1-1 Germany
CitationJournal: Mol Cell / Year: 2024
Title: Non-canonical substrate recognition by the human WDR26-CTLH E3 ligase regulates prodrug metabolism.
Authors: Karthik V Gottemukkala / Jakub Chrustowicz / Dawafuti Sherpa / Sara Sepic / Duc Tung Vu / Özge Karayel / Eleftheria C Papadopoulou / Annette Gross / Kenji Schorpp / Susanne von Gronau / ...Authors: Karthik V Gottemukkala / Jakub Chrustowicz / Dawafuti Sherpa / Sara Sepic / Duc Tung Vu / Özge Karayel / Eleftheria C Papadopoulou / Annette Gross / Kenji Schorpp / Susanne von Gronau / Kamyar Hadian / Peter J Murray / Matthias Mann / Brenda A Schulman / Arno F Alpi /
Abstract: The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic ...The yeast glucose-induced degradation-deficient (GID) E3 ubiquitin ligase forms a suite of complexes with interchangeable receptors that selectively recruit N-terminal degron motifs of metabolic enzyme substrates. The orthologous higher eukaryotic C-terminal to LisH (CTLH) E3 complex has been proposed to also recognize substrates through an alternative subunit, WDR26, which promotes the formation of supramolecular CTLH E3 assemblies. Here, we discover that human WDR26 binds the metabolic enzyme nicotinamide/nicotinic-acid-mononucleotide-adenylyltransferase 1 (NMNAT1) and mediates its CTLH E3-dependent ubiquitylation independently of canonical GID/CTLH E3-family substrate receptors. The CTLH subunit YPEL5 inhibits NMNAT1 ubiquitylation and cellular turnover by WDR26-CTLH E3, thereby affecting NMNAT1-mediated metabolic activation and cytotoxicity of the prodrug tiazofurin. Cryoelectron microscopy (cryo-EM) structures of NMNAT1- and YPEL5-bound WDR26-CTLH E3 complexes reveal an internal basic degron motif of NMNAT1 essential for targeting by WDR26-CTLH E3 and degron mimicry by YPEL5's N terminus antagonizing substrate binding. Thus, our data provide a mechanistic understanding of how YPEL5-WDR26-CTLH E3 acts as a modulator of NMNAT1-dependent metabolism.
History
DepositionAug 8, 2023-
Header (metadata) releaseMay 15, 2024-
Map releaseMay 15, 2024-
UpdateMay 29, 2024-
Current statusMay 29, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18171.png

Downloads & links

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Map

FileDownload / File: emd_18171.map.gz / Format: CCP4 / Size: 5.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
3.59 Å/pix.
x 112 pix.
= 401.744 Å		3.59 Å/pix.
x 112 pix.
= 401.744 Å		3.59 Å/pix.
x 112 pix.
= 401.744 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 3.587 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.04
Minimum - Maximum-0.047387842 - 0.16777174
Average (Standard dev.)0.0030053207 (±0.0148942545)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions112112112
Spacing112112112
CellA=B=C: 401.744 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18171_msk_1.map
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Half map: #1

Fileemd_18171_half_map_1.map
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Half map: #2

Fileemd_18171_half_map_2.map
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Sample components

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Entire : Complex of human WDR26-CTLH E3 ligase bound to YPEL5

EntireName: Complex of human WDR26-CTLH E3 ligase bound to YPEL5
Components
  • Complex: Complex of human WDR26-CTLH E3 ligase bound to YPEL5

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Supramolecule #1: Complex of human WDR26-CTLH E3 ligase bound to YPEL5

SupramoleculeName: Complex of human WDR26-CTLH E3 ligase bound to YPEL5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 900 KDa

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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
DetailsSample mixed with 0.01% beta-OG right before plunging

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 71.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.3000000000000003 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

12542

Final reconstructionResolution.type: BY AUTHOR / Resolution: 11.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 24712
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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