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- EMDB-71891: Human Cullin-4 in complex with CAND2 -

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Basic information

Entry
Database: EMDB / ID: EMD-71891
TitleHuman Cullin-4 in complex with CAND2
Map data
Sample
  • Complex: CAND2-CUL4
    • Protein or peptide: Cullin-4A
    • Protein or peptide: Cullin-associated NEDD8-dissociated protein 2
KeywordsComplex / LIGASE
Function / homology
Function and homology information


SCF complex assembly / negative regulation of granulocyte differentiation / regulation of DNA damage checkpoint / regulation of nucleotide-excision repair / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / hemopoiesis / somatic stem cell population maintenance ...SCF complex assembly / negative regulation of granulocyte differentiation / regulation of DNA damage checkpoint / regulation of nucleotide-excision repair / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / hemopoiesis / somatic stem cell population maintenance / positive regulation of G1/S transition of mitotic cell cycle / intrinsic apoptotic signaling pathway / TBP-class protein binding / T cell activation / G1/S transition of mitotic cell cycle / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Formation of Incision Complex in GG-NER / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / ubiquitin protein ligase activity / rhythmic process / ribosome biogenesis / Neddylation / spermatogenesis / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / cell population proliferation / protein ubiquitination / DNA repair / positive regulation of cell population proliferation / DNA damage response / ubiquitin protein ligase binding / positive regulation of DNA-templated transcription / nucleoplasm / nucleus / cytoplasm / cytosol
Similarity search - Function
TATA-binding protein interacting (TIP20) / Cullin-associated NEDD8-dissociated protein 1/2 / TATA-binding protein interacting (TIP20) / CAND1-like, TPR repeats / HEAT-like repeat / Cullin, N-terminal / Cullin protein neddylation domain / Cullin, conserved site / Cullin alpha solenoid domain / Cullin family signature. ...TATA-binding protein interacting (TIP20) / Cullin-associated NEDD8-dissociated protein 1/2 / TATA-binding protein interacting (TIP20) / CAND1-like, TPR repeats / HEAT-like repeat / Cullin, N-terminal / Cullin protein neddylation domain / Cullin, conserved site / Cullin alpha solenoid domain / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin / : / Cullin alpha+beta domain / Cullin homology domain / Cullin homology domain superfamily / Cullin family profile. / Armadillo-like helical / Armadillo-type fold / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Cullin-associated NEDD8-dissociated protein 2 / Cullin-4A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.38 Å
AuthorsKenny S / Liu X / Das C
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM138016 United States
CitationJournal: Structure / Year: 2026
Title: CAND1 and CAND2 drive CUL4 substrate receptor exchange with largely comparable biochemical efficiency, unlike their relative effects on CUL1.
Authors: Kankan Wang / Sebastian Kenny / Zhana Chagan / Lihong Li / Chittaranjan Das / Xing Liu /
Abstract: Cullin-RING ubiquitin ligases (CRLs) regulate diverse cellular processes by dynamically recruiting substrate receptors onto conserved cullin-RING scaffolds. CAND1 and CAND2 function as substrate ...Cullin-RING ubiquitin ligases (CRLs) regulate diverse cellular processes by dynamically recruiting substrate receptors onto conserved cullin-RING scaffolds. CAND1 and CAND2 function as substrate receptor exchange factors for CRL1, but CAND2 displays reduced efficiency in CRL1 disassembly, exhibits tissue-specific expression, and shows distinct disease associations, raising questions about its function in other CRL subfamilies. Here, we define the regulatory roles of CAND1 and CAND2 in CRL4 remodeling. Using genetic perturbation, real-time kinetic analyses, and quantitative interaction proteomics, we show that both CAND proteins promote CRL4-mediated protein degradation and enhance the dynamic exchange of DDB1·DCAF substrate receptor modules, likely through conserved yet distinct structural features. In contrast to their differential efficiencies in CRL1 disassembly, CAND1 and CAND2 exhibit similar kinetic parameters and comparable exchange efficiencies across most of the CRL4 complexes. These findings establish CAND1 and CAND2 as bona fide CRL4 exchange factors and reveal biochemical distinctions between CRL4 and CRL1 regulation.
History
DepositionAug 1, 2025-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJun 10, 2026-
Current statusJun 10, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_71891.png

Downloads & links

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Map

FileDownload / File: emd_71891.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å		0.86 Å/pix.
x 256 pix.
= 220.16 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.315
Minimum - Maximum-0.52154773 - 1.2960713
Average (Standard dev.)0.008089546 (±0.060316984)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_71891_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_71891_half_map_2.map
Projections & Slices
AxesZYX

Projections

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Histogram

Histogram (log scale)

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Sample components

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Entire : CAND2-CUL4

EntireName: CAND2-CUL4
Components
  • Complex: CAND2-CUL4
    • Protein or peptide: Cullin-4A
    • Protein or peptide: Cullin-associated NEDD8-dissociated protein 2

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Supramolecule #1: CAND2-CUL4

SupramoleculeName: CAND2-CUL4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cullin-4A

MacromoleculeName: Cullin-4A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.592531 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SASAGGSKKL VIKNFRDRPR LPDNYTQDTW RKLHEAVRAV QSSTSIRYNL EELYQAVENL CSHKVSPMLY KQLRQACEDH VQAQILPFR EDSLDSVLFL KKINTCWQDH CRQMIMIRSI FLFLDRTYVL QNSTLPSIWD MGLELFRTHI ISDKMVQSKT I DGILLLIE ...String:
SASAGGSKKL VIKNFRDRPR LPDNYTQDTW RKLHEAVRAV QSSTSIRYNL EELYQAVENL CSHKVSPMLY KQLRQACEDH VQAQILPFR EDSLDSVLFL KKINTCWQDH CRQMIMIRSI FLFLDRTYVL QNSTLPSIWD MGLELFRTHI ISDKMVQSKT I DGILLLIE RERSGEAVDR SLLRSLLGML SDLQVYKDSF ELKFLEETNC LYAAEGQRLM QEREVPEYLN HVSKRLEEEG DR VITYLDH STQKPLIACV EKQLLGEHLT AILQKGLDHL LDENRVPDLA QMYQLFSRVR GGQQALLQHW SEYIKTFGTA IVI NPEKDK DMVQDLLDFK DKVDHVIEVC FQKNERFVNL MKESFETFIN KRPNKPAELI AKHVDSKLRA GNKEATDEEL ERTL DKIMI LFRFIHGKDV FEAFYKKDLA KRLLVGKSAS VDAEKSMLSK LKHECGAAFT SKLEGMFKDM ELSKDIMVHF KQHMQ NQSD SGPIDLTVNI LTMGYWPTYT PMEVHLTPEM IKLQEVFKAF YLGKHSGRKL QWQTTLGHAV LKAEFKEGKK EFQVSL FQT LVLLMFNEGD GFSFEEIKMA TGIEDSELRR TLQSLACGKA RVLIKSPKGK EVEDGDKFIF NGEFKHKLFR IKINQIQ MK ETVEEQVSTT ERVFQDRQYQ IDAAIVRIMK MRKTLGHNLL VSELYNQLKF PVKPGDLKKR IESLIDRDYM ERDKDNPN Q YHYVA

UniProtKB: Cullin-4A

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Macromolecule #2: Cullin-associated NEDD8-dissociated protein 2

MacromoleculeName: Cullin-associated NEDD8-dissociated protein 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 136.6695 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: SAGWSHPQFE KMSTAAFHIS SLLEKMTSSD KDFRFMATSD LMSELQKDSI QLDEDSERKV VKMLLRLLED KNGEVQNLAV KCLGPLVVK VKEYQVETIV DTLCTNMRSD KEQLRDIAGI GLKTVLSELP PAATGSGLAT NVCRKITGQL TSAIAQQEDV A VQLEALDI ...String:
SAGWSHPQFE KMSTAAFHIS SLLEKMTSSD KDFRFMATSD LMSELQKDSI QLDEDSERKV VKMLLRLLED KNGEVQNLAV KCLGPLVVK VKEYQVETIV DTLCTNMRSD KEQLRDIAGI GLKTVLSELP PAATGSGLAT NVCRKITGQL TSAIAQQEDV A VQLEALDI LSDMLSRLGV PLGAFHASLL HCLLPQLSSP RLAVRKRAVG ALGHLAAACS TDLFVELADH LLDRLPGPRV PT SPTAIRT LIQCLGSVGR QAGHRLGAHL DRLVPLVEDF CNLDDDELRE SCLQAFEAFL RKCPKEMGPH VPNVTSLCLQ YIK HDPNYN YDSDEDEEQM ETEDSEFSEQ ESEDEYSDDD DMSWKVRRAA AKCIAALISS RPDLLPDFHC TLAPVLIRRF KERE ENVKA DVFTAYIVLL RQTQPPKGWL EAMEEPTQTG SNLHMLRGQV PLVVKALQRQ LKDRSVRARQ GCFSLLTELA GVLPG SLAE HMPVLVSGII FSLADRSSSS TIRMDALAFL QGLLGTEPAE AFHPHLPILL PPVMACVADS FYKIAAEALV VLQELV RAL WPLHRPRMLD PEPYVGEMSA VTLARLRATD LDQEVKERAI SCMGHLVGHL GDRLGDDLEP TLLLLLDRLR NEITRLP AI KALTLVAVSP LQLDLQPILA EALHILASFL RKNQRALRLA TLAALDALAQ SQGLSLPPSA VQAVLAELPA LVNESDMH V AQLAVDFLAT VTQAQPASLV EVSGPVLSEL LRLLRSPLLP AGVLAAAEGF LQALVGTRPP CVDYAKLISL LTAPVYEQA VDGGPGLHKQ VFHSLARCVA ALSAACPQEA ASTASRLVCD ARSPHSSTGV KVLAFLSLAE VGQVAGPGHQ RELKAVLLEA LGSPSEDVR AAASYALGRV GAGSLPDFLP FLLEQIEAEP RRQYLLLHSL REALGAAQPD SLKPYAEDIW ALLFQRCEGA E EGTRGVVA ECIGKLVLVN PSFLLPRLRK QLAAGRPHTR STVITAVKFL ISDQPHPIDP LLKSFIGEFM ESLQDPDLNV RR ATLAFFN SAVHNKPSLV RDLLDDILPL LYQETKIRRD LIREVEMGPF KHTVDDGLDV RKAAFECMYS LLESCLGQLD ICE FLNHVE DGLKDHYDIR MLTFIMVARL ATLCPAPVLQ RVDRLIEPLR ATCTAKVKAG SVKQEFEKQD ELKRSAMRAV AALL TIPEV GKSPIMADFS SQIRSNPELA ALFESIQKDS ASAPSTDSME LS

UniProtKB: Cullin-associated NEDD8-dissociated protein 2

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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: 7.4
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 5666 / Average exposure time: 3.19 sec. / Average electron dose: 1.52 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3883614
CTF correctionSoftware - Name: cryoSPARC (ver. 3.2.0) / Type: NONE
Startup modelType of model: INSILICO MODEL / In silico model: AlphaFold2 model of CAND2 and Cul4
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.38 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.2.0) / Number images used: 46496
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.2.0)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 3.2.0)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementSpace: REAL / Protocol: RIGID BODY FIT / Target criteria: Cross-correlation coefficient
Output model

PDB-9pvh:
Human Cullin-4 in complex with CAND2

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