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- PDB-8ebl: Structure of KLHDC2 substrate binding domain bound to C-degron fr... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8ebl | |||||||||
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Title | Structure of KLHDC2 substrate binding domain bound to C-degron from EPHB2 | |||||||||
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Function / homology | ![]() ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ![]() ![]() ![]() | |||||||||
![]() | Scott, D.C. / Schulman, B.A. | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 294 KB | Display | ![]() |
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PDB format | ![]() | 234.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 8ebmC ![]() 8ebnC ![]() 6do2S S: Starting model for refinement C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 39764.422 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() #2: Protein/peptide | Mass: 1469.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) ![]() ![]() #3: Water | ChemComp-HOH / | ![]() |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 2.3 Å3/Da / Density % sol: 46.51 % |
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Crystal grow![]() | Temperature: 295 K / Method: vapor diffusion, hanging drop Details: 10-15% PEG3350, 0.2M NaSCN, 0.1 M Bis-Tris Propane, pH = 7.5 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diffraction source | Source: ![]() ![]() ![]() | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Detector | Type: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Dec 8, 2018 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Radiation wavelength | Wavelength![]() | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection | Resolution: 1.37→50 Å / Num. obs: 149088 / % possible obs: 95.8 % / Redundancy: 6.1 % / Biso Wilson estimate: 17.39 Å2 / Rmerge(I) obs: 0.039 / Rpim(I) all: 0.018 / Rrim(I) all: 0.043 / Χ2: 1.04 / Net I/σ(I): 10.3 / Num. measured all: 906211 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reflection shell | Diffraction-ID: 1
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Processing
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Refinement | Method to determine structure![]() ![]() Starting model: 6DO2 Resolution: 1.37→33.44 Å / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 17.14 / Stereochemistry target values: ML
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 76.95 Å2 / Biso mean: 25.9782 Å2 / Biso min: 10.29 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: final / Resolution: 1.37→33.44 Å
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LS refinement shell | Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 30
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