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- EMDB-36131: Structure of CRL2APPBP2 bound with RxxGP degron (tetramer) -

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Basic information

Entry
Database: EMDB / ID: EMD-36131
TitleStructure of CRL2APPBP2 bound with RxxGP degron (tetramer)
Map data
Sample
  • Complex: CRL2APPBP2 E3 liganse
    • Protein or peptide: Amyloid protein-binding protein 2
    • Protein or peptide: Cullin-2CUL2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: XP_211896 C-degron
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Ligand: ZINC ION
KeywordsE3 Ubiquitination ligase / PROTEIN BINDING
Function / homology
Function and homology information


cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / elongin complex / VCB complex ...cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / microtubule associated complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / negative regulation of type I interferon production / microtubule motor activity / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul3-RING ubiquitin ligase complex / Prolactin receptor signaling / protein monoubiquitination / 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 / ubiquitin-like ligase-substrate adaptor activity / intracellular transport / protein K48-linked ubiquitination / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / Nuclear events stimulated by ALK signaling in cancer / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / positive regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / Regulation of BACH1 activity / T cell activation / post-translational protein modification / intrinsic apoptotic signaling pathway / transcription corepressor binding / Degradation of DVL / transcription elongation by RNA polymerase II / Recognition of DNA damage by PCNA-containing replication complex / transcription initiation at RNA polymerase II promoter / cellular response to amino acid stimulus / TP53 Regulates Transcription of DNA Repair Genes / Degradation of GLI1 by the proteasome / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / DNA Damage Recognition in GG-NER / intracellular protein transport / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / G1/S transition of mitotic cell cycle / negative regulation of canonical Wnt signaling pathway / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / cytoplasmic vesicle membrane / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / 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 / Formation of Incision Complex in GG-NER / Regulation of expression of SLITs and ROBOs / Interleukin-1 signaling / Dual incision in TC-NER / protein polyubiquitination / Orc1 removal from chromatin / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of RAS by GAPs / ubiquitin-protein transferase activity / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / cellular response to UV / ubiquitin protein ligase activity / KEAP1-NFE2L2 pathway / MAPK cascade / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / ubiquitin-dependent protein catabolic process / spermatogenesis / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly
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 / Cullin family signature. / Elongin B / Cullin ...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 / Cullin family signature. / Elongin B / Cullin / Elongin-C / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / 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. / SKP1/BTB/POZ domain superfamily / Tetratricopeptide repeats / Tetratricopeptide repeat / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Tetratricopeptide-like helical domain superfamily / Ubiquitin-like domain superfamily / Zinc finger, RING/FYVE/PHD-type / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsZhao S / Zhang K / Xu C
Funding support China, 1 items
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, 2023-
Header (metadata) releaseOct 18, 2023-
Map releaseOct 18, 2023-
UpdateOct 25, 2023-
Current statusOct 25, 2023Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36131.png

Downloads & links

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Map

FileDownload / File: emd_36131.map.gz / Format: CCP4 / Size: 536.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.82 Å
Density
Contour LevelBy AUTHOR: 0.07
Minimum - Maximum-0.96477175 - 1.4381789
Average (Standard dev.)0.00012134361 (±0.021636322)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions520520520
Spacing520520520
CellA=B=C: 426.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36131_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36131_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : CRL2APPBP2 E3 liganse

EntireName: CRL2APPBP2 E3 liganse
Components
  • Complex: CRL2APPBP2 E3 liganse
    • Protein or peptide: Amyloid protein-binding protein 2
    • Protein or peptide: Cullin-2CUL2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: XP_211896 C-degron
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1, N-terminally processed
  • Ligand: ZINC ION

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Supramolecule #1: CRL2APPBP2 E3 liganse

SupramoleculeName: CRL2APPBP2 E3 liganse / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 400 kDa/nm

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Macromolecule #1: Amyloid protein-binding protein 2

MacromoleculeName: Amyloid protein-binding protein 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.258508 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAAVELEWIP ETLYNTAISA VVDNYIRSRR DIRSLPENIQ FDVYYKLYQQ GRLCQLGSEF CELEVFAKVL RALDKRHLLH HCFQALMDH GVKVASVLAY SFSRRCSYIA ESDAAVKEKA IQVGFVLGGF LSDAGWYSDA EKVFLSCLQL CTLHDEMLHW F RAVECCVR ...String:
MAAVELEWIP ETLYNTAISA VVDNYIRSRR DIRSLPENIQ FDVYYKLYQQ GRLCQLGSEF CELEVFAKVL RALDKRHLLH HCFQALMDH GVKVASVLAY SFSRRCSYIA ESDAAVKEKA IQVGFVLGGF LSDAGWYSDA EKVFLSCLQL CTLHDEMLHW F RAVECCVR LLHVRNGNCK YHLGEETFKL AQTYMDKLSK HGQQANKAAL YGELCALLFA KSHYDEAYKW CIEAMKEITA GL PVKVVVD VLRQASKACV VKREFKKAEQ LIKHAVYLAR DHFGSKHPKY SDTLLDYGFY LLNVDNICQS VAIYQAALDI RQS VFGGKN IHVATAHEDL AYSSYVHQYS SGKFDNALFH AERAIGIITH ILPEDHLLLA SSKRVKALIL EEIAIDCHNK ETEQ RLLQE AHDLHLSSLQ LAKKAFGEFN VQTAKHYGNL GRLYQSMRKF KEAEEMHIKA IQIKEQLLGQ EDYEVALSVG HLASL YNYD MNQYENAEKL YLRSIAIGKK LFGEGYSGLE YDYRGLIKLY NSIGNYEKVF EYHNVLSNWN RLRDRQYSVT DALEDV STS PQSTEEVVQS FLISQ

UniProtKB: Amyloid protein-binding protein 2

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Macromolecule #2: Cullin-2

MacromoleculeName: Cullin-2 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 87.068836 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: TSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK ...String:
TSLKPRVVDF DETWNKLLTT IKAVVMLEYV ERATWNDRFS DIYALCVAYP EPLGERLYTE TKIFLENHVR HLHKRVLESE EQVLVMYHR YWEEYSKGAD YMDCLYRYLN TQFIKKNKLT EADLQYGYGG VDMNEPLMEI GELALDMWRK LMVEPLQAIL I RMLLREIK NDRGGEDPNQ KVIHGVINSF VHVEQYKKKF PLKFYQEIFE SPFLTETGEY YKQEASNLLQ ESNCSQYMEK VL GRLKDEE IRCRKYLHPS SYTKVIHECQ QRMVADHLQF LHAECHNIIR QEKKNDMANM YVLLRAVSTG LPHMIQELQN HIH DEGLRA TSNLTQENMP TLFVESVLEV HGKFVQLINT VLNGDQHFMS ALDKALTSVV NYREPKSVCK APELLAKYCD NLLK KSAKG MTENEVEDRL TSFITVFKYI DDKDVFQKFY ARMLAKRLIH GLSMSMDSEE AMINKLKQAC GYEFTSKLHR MYTDM SVSA DLNNKFNNFI KNQDTVIDLG ISFQIYVLQA GAWPLTQAPS STFAIPQELE KSVQMFELFY SQHFSGRKLT WLHYLC TGE VKMNYLGKPY VAMVTTYQMA VLLAFNNSET VSYKELQDST QMNEKELTKT IKSLLDVKMI NHDSEKEDID AESSFSL NM NFSSKRTKFK ITTSMQKDTP QEMEQTRSAV DEDRKMYLQA AIVRIMKARK VLRHNALIQE VISQSRARFN PSISMIKK C IEVLIDKQYI ERSQASADEY SYVA

UniProtKB: Cullin-2

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Macromolecule #3: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.147781 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMKPQDSG SSANEQAVQ

UniProtKB: Elongin-B

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Macromolecule #4: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.84342 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MYVKLISSDG HEFIVKREHA LTSGTIKAML SGPGQFAENE TNEVNFREIP SHVLSKVCMY FTYKVRYTNS STEIPEFPIA PEIALELLM AANFLDC

UniProtKB: Elongin-C

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Macromolecule #5: XP_211896 C-degron

MacromoleculeName: XP_211896 C-degron / type: protein_or_peptide / ID: 5 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.771074 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TVPTLTRGRL TRNKGP

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Macromolecule #6: E3 ubiquitin-protein ligase RBX1, N-terminally processed

MacromoleculeName: E3 ubiquitin-protein ligase RBX1, N-terminally processed
type: protein_or_peptide / ID: 6 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.289977 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAAAMDVDTP SGTNSGAGKK RFEVKKWNAV ALWAWDIVVD NCAICRNHIM DLCIECQANQ ASATSEECTV AWGVCNHAFH FHCISRWLK TRQVCPLDNR EWEFQKYGH

UniProtKB: E3 ubiquitin-protein ligase RBX1

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Macromolecule #7: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 7 / Number of copies: 8 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Model from alphafold
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 258495

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