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- PDB-8jav: Structure of CRL2APPBP2 bound with the C-degron of MRPL28 (tetramer) -

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Basic information

Entry
Database: PDB / ID: 8jav
TitleStructure of CRL2APPBP2 bound with the C-degron of MRPL28 (tetramer)
Components
  • Amyloid protein-binding protein 2
  • Cullin-2
  • E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Elongin-B
  • Elongin-C
  • MRPL28 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 / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy / regulation of xenophagy / target-directed miRNA degradation / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / elongin complex ...negative regulation of beige fat cell differentiation / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / negative regulation of mitophagy / regulation of xenophagy / target-directed miRNA degradation / cellular response to chemical stress / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / elongin complex / Cul7-RING ubiquitin ligase complex / VCB complex / regulation of cell cycle process / neural crest cell differentiation / RNA polymerase II transcription initiation surveillance / positive regulation of protein autoubiquitination / protein neddylation / microtubule motor activity / regulation of BMP signaling pathway / NEDD8 ligase activity / regulation of mitophagy / microtubule associated complex / negative regulation of response to oxidative stress / regulation of centrosome duplication / protein K27-linked ubiquitination / positive regulation of cilium assembly / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / regulation of TOR signaling / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / negative regulation of DNA-templated DNA replication / SCF ubiquitin ligase complex / regulation of DNA damage checkpoint / regulation of mitotic cytokinesis / negative regulation of type I interferon production / Cul3-RING ubiquitin ligase complex / regulation of miRNA-mediated gene silencing / regulation of natural killer cell activation / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Prolactin receptor signaling / nucleotide-excision repair complex / regulation of cell cycle phase transition / Cul4-RING E3 ubiquitin ligase complex / regulation of stem cell population maintenance / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of adipose tissue development / intracellular transport / Cul4B-RING E3 ubiquitin ligase complex / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of cellular response to stress / limb development / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / protein monoubiquitination / cullin family protein binding / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / centrosome duplication / regulation of DNA-templated DNA replication initiation / Formation of HIV elongation complex in the absence of HIV Tat / cilium assembly / RNA Polymerase II Transcription Elongation / ubiquitin-like ligase-substrate adaptor activity / 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 / protein K63-linked ubiquitination / RNA Polymerase II Pre-transcription Events / Nuclear events stimulated by ALK signaling in cancer / regulation of cellular response to insulin stimulus / protein K48-linked ubiquitination / transcription-coupled nucleotide-excision repair / post-translational protein modification / positive regulation of TORC1 signaling / regulation of embryonic development / replication fork processing / cellular response to amino acid stimulus / transcription corepressor binding / regulation of mitotic cell cycle / negative regulation of canonical NF-kappaB signal transduction / rescue of stalled cytosolic ribosome / site of DNA damage / negative regulation of canonical Wnt signaling pathway / Regulation of BACH1 activity / T cell activation / negative regulation of smoothened signaling pathway / G1/S transition of mitotic cell cycle / TP53 Regulates Transcription of DNA Repair Genes / intracellular protein transport / protein processing / epigenetic regulation of gene expression / transcription initiation at RNA polymerase II promoter / Degradation of DVL / Degradation of CRY and PER proteins / cytoplasmic vesicle membrane
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: 3.44 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 7, 2023Deposition site: PDBJ / Processing site: PDBC
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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: MRPL28 C-degron
B: Amyloid protein-binding protein 2
F: MRPL28 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: MRPL28 C-degron
P: MRPL28 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)743,80830
Polymers743,28522
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: 66945.258 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
MRPL28 C-degron


Mass: 1670.864 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: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113976 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00440194
ELECTRON MICROSCOPYf_angle_d0.51154245
ELECTRON MICROSCOPYf_dihedral_angle_d4.1685302
ELECTRON MICROSCOPYf_chiral_restr0.045942
ELECTRON MICROSCOPYf_plane_restr0.0046916

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