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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


cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / VCB complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / elongin complex ...cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / VCB complex / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / elongin complex / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / microtubule motor activity / negative regulation of response to oxidative stress / microtubule associated complex / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / Cul4A-RING E3 ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of mitophagy / Prolactin receptor signaling / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / protein monoubiquitination / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / intracellular transport / Formation of HIV elongation complex in the absence of HIV Tat / protein K48-linked ubiquitination / RNA Polymerase II Transcription Elongation / Nuclear events stimulated by ALK signaling in cancer / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / regulation of cellular response to insulin stimulus / positive regulation of TORC1 signaling / negative regulation of insulin receptor signaling pathway / post-translational protein modification / intrinsic apoptotic signaling pathway / cytoplasmic vesicle membrane / T cell activation / Regulation of BACH1 activity / transcription corepressor binding / intracellular protein transport / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / cellular response to amino acid stimulus / Degradation of DVL / transcription elongation by RNA polymerase II / Degradation of GLI1 by the proteasome / Recognition of DNA damage by PCNA-containing replication complex / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / negative regulation of canonical Wnt signaling pathway / Negative regulation of NOTCH4 signaling / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Inactivation of CSF3 (G-CSF) signaling / DNA Damage Recognition in GG-NER / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / NOTCH1 Intracellular Domain Regulates Transcription / Formation of TC-NER Pre-Incision Complex / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / G1/S transition of mitotic cell cycle / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / Interleukin-1 signaling / Orc1 removal from chromatin / Dual incision in TC-NER / Regulation of RAS by GAPs / protein polyubiquitination / positive regulation of protein catabolic process / Gap-filling DNA repair synthesis and ligation in TC-NER / ubiquitin-protein transferase activity / Regulation of RUNX2 expression and activity / cellular response to UV / KEAP1-NFE2L2 pathway / ubiquitin protein ligase activity / MAPK cascade / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation
Similarity search - Function
Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Tetratricopeptide repeat / Cullin protein neddylation domain / : / Cullin, conserved site / Elongin-C / Cullin family signature. ...Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Tetratricopeptide repeat / Cullin protein neddylation domain / : / Cullin, conserved site / Elongin-C / Cullin family signature. / Elongin B / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / 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 / SKP1/BTB/POZ domain superfamily / Tetratricopeptide repeat / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin family / Ubiquitin homologues / Tetratricopeptide-like helical domain superfamily / 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
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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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

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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
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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