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- EMDB-16370: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry -

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Entry
Database: EMDB / ID: EMD-16370
TitleStructure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
Map datarelion postprocess
Sample
  • Complex: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
Keywordscullin-RING E3 ubiquitin ligase / LIGASE / ubiquitin / KLHDC2 / C-degron / CUL2
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 8.2 Å
AuthorsScott DC / King M / Baek K / Schulman BA
Funding support Germany, European Union, 2 items
OrganizationGrant numberCountry
Max Planck Society Germany
European Research Council (ERC)789016European Union
CitationJournal: Mol Cell / Year: 2023
Title: E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
Authors: Daniel C Scott / Moeko T King / Kheewoong Baek / Clifford T Gee / Ravi Kalathur / Jerry Li / Nicholas Purser / Amanda Nourse / Sergio C Chai / Sivaraja Vaithiyalingam / Taosheng Chen / ...Authors: Daniel C Scott / Moeko T King / Kheewoong Baek / Clifford T Gee / Ravi Kalathur / Jerry Li / Nicholas Purser / Amanda Nourse / Sergio C Chai / Sivaraja Vaithiyalingam / Taosheng Chen / Richard E Lee / Stephen J Elledge / Gary Kleiger / Brenda A Schulman /
Abstract: E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins ...E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins with terminal degron-like sequences remains unclear. Here, we report that human KLHDC2, a CRL2 substrate receptor targeting C-terminal Gly-Gly degrons, is regulated through interconversion between two assemblies. In the self-inactivated homotetramer, KLHDC2's C-terminal Gly-Ser motif mimics a degron and engages the substrate-binding domain of another protomer. True substrates capture the monomeric CRL2, driving E3 activation by neddylation and subsequent substrate ubiquitylation. Non-substrates such as NEDD8 bind KLHDC2 with high affinity, but its slow on rate prevents productive association with CRL2. Without substrate, neddylated CRL2 assemblies are deactivated via distinct mechanisms: the monomer by deneddylation and the tetramer by auto-ubiquitylation. Thus, substrate specificity is amplified by KLHDC2 self-assembly acting like a molecular timer, where only bona fide substrates may bind before E3 ligase inactivation.
History
DepositionDec 18, 2022-
Header (metadata) releaseMar 8, 2023-
Map releaseMar 8, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16370.png

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Map

FileDownload / File: emd_16370.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationrelion postprocess
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Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.89 Å/pix.
x 160 pix.
= 301.6 Å		1.89 Å/pix.
x 160 pix.
= 301.6 Å		1.89 Å/pix.
x 160 pix.
= 301.6 Å

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.885 Å
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Contour LevelBy AUTHOR: 0.02
Minimum - Maximum-0.03412285 - 0.09753896
Average (Standard dev.)0.0006401386 (±0.0047977194)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 301.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_16370_msk_1.map
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Additional map: 3d refinement

Fileemd_16370_additional_1.map
Annotation3d refinement
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Half map: halfmap1

Fileemd_16370_half_map_1.map
Annotationhalfmap1
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Half map: halfmap2

Fileemd_16370_half_map_2.map
Annotationhalfmap2
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Sample components

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Entire : Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry

EntireName: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
Components
  • Complex: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry

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Supramolecule #1: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry

SupramoleculeName: Structure of CUL2-KLHDC2 E3 ligase autoinhibited by C-degron mimicry
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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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

Concentration2 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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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: 3.0 µm / Nominal defocus min: 1.5 µm
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: INSILICO MODEL
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 8.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 25185
FSC plot (resolution estimation)

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