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- EMDB-18207: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc3... -

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Entry
Database: EMDB / ID: EMD-18207
TitleUbiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide, Glacios map
Map dataDeepEMhancer map
Sample
  • Complex: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide
KeywordsUbiquitin / Ubiquitin priming / mono-ubiquitination / CUL2 / UBE2R2 / CDC34 / ELOB/C / FEM1C / monoubiquitination cullin / CRL / cullin-RING ligase / E3 / UBE2R / LIGASE / SIL1
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.46 Å
AuthorsLiwocha J / Prabu JR / Kleiger G / Schulman BA
Funding support Germany, 1 items
OrganizationGrant numberCountry
Max Planck Society Germany
CitationJournal: Mol Cell / Year: 2024
Title: Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting.
Authors: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / ...Authors: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / Senthil K Radhakrishnan / Donald S Kirkpatrick / Kurt M Reichermeier / Brenda A Schulman / Gary Kleiger /
Abstract: Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. ...Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation.
History
DepositionAug 16, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateApr 17, 2024-
Current statusApr 17, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18207.png

Downloads & links

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Map

FileDownload / File: emd_18207.map.gz / Format: CCP4 / Size: 18.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDeepEMhancer map
Voxel sizeX=Y=Z: 1.885 Å
Density
Contour LevelBy AUTHOR: 0.0112
Minimum - Maximum-0.0017201905 - 1.5122349
Average (Standard dev.)0.0013597525 (±0.02575194)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions168168168
Spacing168168168
CellA=B=C: 316.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18207_msk_1.map
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AxesZYX

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Additional map: Relion postprocessed map

Fileemd_18207_additional_1.map
AnnotationRelion postprocessed map
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Half map: #1

Fileemd_18207_half_map_1.map
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Half map: #2

Fileemd_18207_half_map_2.map
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Sample components

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Entire : Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc3...

EntireName: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide
Components
  • Complex: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide

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Supramolecule #1: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc3...

SupramoleculeName: Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 210 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-PROPANE

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Electron microscopy

MicroscopeTFS GLACIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.2 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 22000
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

10585

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 6.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 70503
FSC plot (resolution estimation)

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