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- PDB-8jaq: Structure of CRL2APPBP2 bound with RxxGP degron (tetramer) -

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Basic information

Entry
Database: PDB / ID: 8jaq
TitleStructure of CRL2APPBP2 bound with RxxGP degron (tetramer)
Components
  • Amyloid protein-binding protein 2
  • Cullin-2
  • E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Elongin-B
  • Elongin-C
  • XP_211896 C-degron
KeywordsPROTEIN BINDING / E3 Ubiquitination ligase
Function / homology
Function and homology information


negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex ...negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / negative regulation of mitophagy / cullin-RING ubiquitin ligase complex / regulation of xenophagy / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / elongin complex / regulation of cell cycle process / neural crest cell differentiation / RNA polymerase II transcription initiation surveillance / positive regulation of protein autoubiquitination / protein neddylation / regulation of BMP signaling pathway / NEDD8 ligase activity / microtubule associated complex / regulation of mitophagy / microtubule motor activity / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / VCB complex / Cul5-RING ubiquitin ligase complex / regulation of TOR signaling / ubiquitin-ubiquitin ligase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / regulation of mitotic cytokinesis / Cul3-RING ubiquitin ligase complex / regulation of DNA damage checkpoint / negative regulation of type I interferon production / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Prolactin receptor signaling / regulation of cell cycle phase transition / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / regulation of cellular response to stress / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / limb development / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / intracellular transport / protein monoubiquitination / cullin family protein binding / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / regulation of DNA-templated DNA replication initiation / centrosome duplication / Formation of HIV elongation complex in the absence of HIV Tat / cilium assembly / ubiquitin-like ligase-substrate adaptor activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / intrinsic apoptotic signaling pathway / ribosome-associated ubiquitin-dependent protein catabolic process / signal transduction in response to DNA damage / negative regulation of insulin receptor signaling pathway / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / RNA Polymerase II Pre-transcription Events / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / transcription-coupled nucleotide-excision repair / post-translational protein modification / cellular response to amino acid stimulus / regulation of embryonic development / cytoplasmic vesicle membrane / replication fork processing / transcription corepressor binding / negative regulation of canonical NF-kappaB signal transduction / rescue of stalled cytosolic ribosome / regulation of mitotic cell cycle / site of DNA damage / Regulation of BACH1 activity / T cell activation / TP53 Regulates Transcription of DNA Repair Genes / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / transcription initiation at RNA polymerase II promoter / epigenetic regulation of gene expression / Degradation of DVL / Degradation of CRY and PER proteins / intracellular protein transport / nucleotide-excision repair / transcription elongation by RNA polymerase II / Degradation of GLI1 by the proteasome / regulation of autophagy / Recognition of DNA damage by PCNA-containing replication complex
Similarity search - Function
Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Elongin-C / Elongin B / : / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. ...Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Elongin-C / Elongin B / : / Cullin protein neddylation domain / Cullin, conserved site / Cullin family signature. / Cullin, N-terminal / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin alpha solenoid domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / TPR repeat region circular profile. / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / SKP1/BTB/POZ domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin family / Tetratricopeptide-like helical domain superfamily / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / Cullin-2 / Elongin-C / Elongin-B / Amyloid protein-binding protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsZhao, S. / Zhang, K. / Xu, C.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Molecular basis for C-degron recognition by CRL2 ubiquitin ligase.
Authors: Shidong Zhao / Diana Olmayev-Yaakobov / Wenwen Ru / Shanshan Li / Xinyan Chen / Jiahai Zhang / Xuebiao Yao / Itay Koren / Kaiming Zhang / Chao Xu /
Abstract: E3 ubiquitin ligases determine the specificity of eukaryotic protein degradation by selective binding to destabilizing protein motifs, termed degrons, in substrates for ubiquitin-mediated proteolysis. ...E3 ubiquitin ligases determine the specificity of eukaryotic protein degradation by selective binding to destabilizing protein motifs, termed degrons, in substrates for ubiquitin-mediated proteolysis. The exposed C-terminal residues of proteins can act as C-degrons that are recognized by distinct substrate receptors (SRs) as part of dedicated cullin-RING E3 ubiquitin ligase (CRL) complexes. APPBP2, an SR of Cullin 2-RING ligase (CRL2), has been shown to recognize R-x-x-G/C-degron; however, the molecular mechanism of recognition remains elusive. By solving several cryogenic electron microscopy structures of active CRL2 bound with different R-x-x-G/C-degrons, we unveiled the molecular mechanisms underlying the assembly of the CRL2 dimer and tetramer, as well as C-degron recognition. The structural study, complemented by binding experiments and cell-based assays, demonstrates that APPBP2 specifically recognizes the R-x-x-G/C-degron via a bipartite mechanism; arginine and glycine, which play critical roles in C-degron recognition, accommodate distinct pockets that are spaced by two residues. In addition, the binding pocket is deep enough to enable the interaction of APPBP2 with the motif placed at or up to three residues upstream of the C-end. Overall, our study not only provides structural insight into CRL2-mediated protein turnover but also serves as the basis for future structure-based chemical probe design.
History
DepositionMay 6, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Amyloid protein-binding protein 2
E: Cullin-2
C: Elongin-B
D: Elongin-C
S: XP_211896 C-degron
B: Amyloid protein-binding protein 2
F: XP_211896 C-degron
G: Elongin-B
H: Elongin-C
I: Cullin-2
R: E3 ubiquitin-protein ligase RBX1, N-terminally processed
J: Amyloid protein-binding protein 2
K: Amyloid protein-binding protein 2
L: Cullin-2
M: Elongin-B
N: Elongin-C
O: XP_211896 C-degron
P: XP_211896 C-degron
Q: Elongin-B
T: Elongin-C
V: E3 ubiquitin-protein ligase RBX1, N-terminally processed
U: Cullin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)741,46230
Polymers740,93822
Non-polymers5238
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 18 molecules ABJKEILUCGMQDHNTRV

#1: Protein
Amyloid protein-binding protein 2 / Amyloid beta precursor protein-binding protein 2 / APP-BP2 / Protein interacting with APP tail 1


Mass: 66258.508 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APPBP2, KIAA0228, PAT1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q92624
#2: Protein
Cullin-2 / CUL-2


Mass: 87068.836 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q13617
#3: Protein
Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15370
#4: Protein
Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10843.420 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15369
#6: Protein E3 ubiquitin-protein ligase RBX1, N-terminally processed / E3 ubiquitin-protein transferase RBX1 / N-terminally processed


Mass: 12289.977 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Escherichia coli (E. coli) / References: UniProt: P62877

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Protein/peptide / Non-polymers , 2 types, 12 molecules SFOP

#5: Protein/peptide
XP_211896 C-degron


Mass: 1771.074 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#7: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CRL2APPBP2 E3 liganse / Type: COMPLEX / Entity ID: #1-#6 / Source: MULTIPLE SOURCES
Molecular weightValue: 400 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 258495 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00340078
ELECTRON MICROSCOPYf_angle_d0.53554094
ELECTRON MICROSCOPYf_dihedral_angle_d4.2435284
ELECTRON MICROSCOPYf_chiral_restr0.0395934
ELECTRON MICROSCOPYf_plane_restr0.0046889

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