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- EMDB-36135: Structure of CRL2APPBP2 bound with the C-degron of MRPL28 (tetramer) -

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Basic information

Entry
Database: EMDB / ID: EMD-36135
TitleStructure of CRL2APPBP2 bound with the C-degron of MRPL28 (tetramer)
Map data
Sample
  • Complex: CRL2APPBP2 E3 liganse
    • Protein or peptide: Amyloid protein-binding protein 2
    • Protein or peptide: Cullin-2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: MRPL28 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


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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.44 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-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36135.png

Downloads & links

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Map

FileDownload / File: emd_36135.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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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

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Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.6577465 - 1.007895
Average (Standard dev.)0.0006976371 (±0.018583998)
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: #2

Fileemd_36135_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_36135_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: Cullin-2
    • Protein or peptide: Elongin-B
    • Protein or peptide: Elongin-C
    • Protein or peptide: MRPL28 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: 66.945258 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 FLISQNVEGP SC

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: MRPL28 C-degron

MacromoleculeName: MRPL28 C-degron / type: protein_or_peptide / ID: 5 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.670864 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QALSEPAVVQ KRASGQ

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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
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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER / Details: Model from alphafold
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 113976
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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