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- EMDB-36132: Structure of CRL2APPBP2 bound with RxxGPAA degron (dimer) -

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Basic information

Entry
Database: EMDB / ID: EMD-36132
TitleStructure of CRL2APPBP2 bound with RxxGPAA degron (dimer)
Map data
Sample
  • Complex: CRL2APPBP2 E3 liganse
    • Protein or peptide: Amyloid protein-binding protein 2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: XP_211896+AA C-degron
    • Protein or peptide: Cullin-2
  • Ligand: ZINC ION
KeywordsE3 Ubiquitination ligase / PROTEIN BINDING
Function / homology
Function and homology information


ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / elongin complex / VCB complex / Cul5-RING ubiquitin ligase complex / microtubule associated complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / microtubule motor activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process ...ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / elongin complex / VCB complex / Cul5-RING ubiquitin ligase complex / microtubule associated complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / microtubule motor activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / ubiquitin ligase complex scaffold activity / 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 / Tat-mediated elongation of the HIV-1 transcript / intracellular transport / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / intrinsic apoptotic signaling pathway / transcription corepressor binding / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / intracellular protein transport / Vif-mediated degradation of APOBEC3G / cytoplasmic vesicle membrane / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / ubiquitin-protein transferase activity / G1/S transition of mitotic cell cycle / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / protein-macromolecule adaptor activity / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / microtubule / protein ubiquitination / ubiquitin protein ligase binding / protein-containing complex binding / regulation of transcription by RNA polymerase II / nucleolus / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Tetratricopeptide repeat / Cullin protein neddylation domain / Elongin B / Elongin-C / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain ...Amyloid protein-binding protein 2 / Tetratricopeptide repeat / Tetratricopeptide repeat / Cullin protein neddylation domain / Elongin B / Elongin-C / Cullin, conserved site / Cullin family signature. / 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. / SKP1/BTB/POZ domain superfamily / Tetratricopeptide repeats / Tetratricopeptide repeat / Ubiquitin family / Ubiquitin homologues / Tetratricopeptide-like helical domain superfamily / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Cullin-2 / Elongin-C / Elongin-B / Amyloid protein-binding protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 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 7, 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_36132.png

Downloads & links

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Map

FileDownload / File: emd_36132.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 512 pix.
= 419.84 Å		0.82 Å/pix.
x 512 pix.
= 419.84 Å		0.82 Å/pix.
x 512 pix.
= 419.84 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.8213588 - 1.366889
Average (Standard dev.)0.00037890935 (±0.019286795)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 419.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36132_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_36132_half_map_2.map
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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: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: XP_211896+AA C-degron
    • Protein or peptide: Cullin-2
  • 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-#5
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: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.372609 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 FLISQN

UniProtKB: Amyloid protein-binding protein 2

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Macromolecule #2: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 2 / Number of copies: 2 / 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 #3: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 3 / Number of copies: 2 / 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 #4: XP_211896+AA C-degron

MacromoleculeName: XP_211896+AA C-degron / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.91323 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
TVPTLTRGRL TRNKGPAA

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Macromolecule #5: Cullin-2

MacromoleculeName: Cullin-2 / type: protein_or_peptide / ID: 5 / Number of copies: 2 / 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 #6: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 6 / Number of copies: 1 / 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
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Model from alphafold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 143118
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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