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- EMDB-18214: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric as... -

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Entry
Database: EMDB / ID: EMD-18214
TitleStructure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric assembly
Map datapostprocess map
Sample
  • Complex: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric assembly
    • Protein or peptide: Cullin-9
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1
KeywordsCullin-RING RBR E3 Ligase / LIGASE
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 / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity ...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 / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / Cul5-RING ubiquitin ligase 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 / Cul4B-RING E3 ubiquitin ligase complex / regulation of mitotic nuclear division / Cul3-RING ubiquitin ligase complex / Prolactin receptor signaling / protein monoubiquitination / cullin family protein binding / protein K48-linked ubiquitination / Nuclear events stimulated by ALK signaling in cancer / positive regulation of TORC1 signaling / Regulation of BACH1 activity / T cell activation / post-translational protein modification / Degradation of DVL / Recognition of DNA damage by PCNA-containing replication complex / cellular response to amino acid stimulus / 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 / 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 / RING-type E3 ubiquitin transferase / Degradation of beta-catenin by the destruction complex / negative regulation of canonical Wnt signaling pathway / 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 / microtubule cytoskeleton organization / Formation of TC-NER Pre-Incision Complex / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Regulation of expression of SLITs and ROBOs / Formation of Incision Complex in GG-NER / Interleukin-1 signaling / protein polyubiquitination / Orc1 removal from chromatin / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Regulation of RAS by GAPs / 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 / 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 / positive regulation of canonical NF-kappaB signal transduction / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / molecular adaptor activity / protein ubiquitination / DNA repair / DNA damage response / ubiquitin protein ligase binding / zinc ion binding / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
: / : / : / CPH domain / Mouse development and cellular proliferation protein Cullin-7 / IBR domain, a half RING-finger domain / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) / DOC domain profile. / Anaphase-promoting complex, subunit 10 (APC10) ...: / : / : / CPH domain / Mouse development and cellular proliferation protein Cullin-7 / IBR domain, a half RING-finger domain / APC10/DOC domain / Anaphase-promoting complex, subunit 10 (APC10) / DOC domain profile. / Anaphase-promoting complex, subunit 10 (APC10) / IBR domain / In Between Ring fingers / TRIAD supradomain / TRIAD supradomain profile. / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / Cullin, conserved site / Cullin family signature. / Cullin / Cullin protein, neddylation domain / Cullin protein neddylation domain / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Galactose-binding-like domain superfamily / Zinc finger RING-type profile. / Zinc finger, RING-type / Armadillo-like helical / Ribosomal protein L2, domain 2 / Armadillo-type fold / Zinc finger, RING/FYVE/PHD-type / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
E3 ubiquitin-protein ligase RBX1 / Cullin-9
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsHopf LVM / Horn-Ghetko D / Schulman BA
Funding supportEuropean Union, Germany, 2 items
OrganizationGrant numberCountry
European Research Council (ERC)789016European Union
Max Planck Society Germany
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Noncanonical assembly, neddylation and chimeric cullin-RING/RBR ubiquitylation by the 1.8 MDa CUL9 E3 ligase complex.
Authors: Daniel Horn-Ghetko / Linus V M Hopf / Ishita Tripathi-Giesgen / Jiale Du / Sebastian Kostrhon / D Tung Vu / Viola Beier / Barbara Steigenberger / J Rajan Prabu / Luca Stier / Elias M Bruss / ...Authors: Daniel Horn-Ghetko / Linus V M Hopf / Ishita Tripathi-Giesgen / Jiale Du / Sebastian Kostrhon / D Tung Vu / Viola Beier / Barbara Steigenberger / J Rajan Prabu / Luca Stier / Elias M Bruss / Matthias Mann / Yue Xiong / Brenda A Schulman /
Abstract: Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with ...Ubiquitin ligation is typically executed by hallmark E3 catalytic domains. Two such domains, 'cullin-RING' and 'RBR', are individually found in several hundred human E3 ligases, and collaborate with E2 enzymes to catalyze ubiquitylation. However, the vertebrate-specific CUL9 complex with RBX1 (also called ROC1), of interest due to its tumor suppressive interaction with TP53, uniquely encompasses both cullin-RING and RBR domains. Here, cryo-EM, biochemistry and cellular assays elucidate a 1.8-MDa hexameric human CUL9-RBX1 assembly. Within one dimeric subcomplex, an E2-bound RBR domain is activated by neddylation of its own cullin domain and positioning from the adjacent CUL9-RBX1 in trans. Our data show CUL9 as unique among RBX1-bound cullins in dependence on the metazoan-specific UBE2F neddylation enzyme, while the RBR domain protects it from deneddylation. Substrates are recruited to various upstream domains, while ubiquitylation relies on both CUL9's neddylated cullin and RBR domains achieving self-assembled and chimeric cullin-RING/RBR E3 ligase activity.
History
DepositionAug 16, 2023-
Header (metadata) releaseApr 17, 2024-
Map releaseApr 17, 2024-
UpdateApr 24, 2024-
Current statusApr 24, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_18214.png

Downloads & links

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Map

FileDownload / File: emd_18214.map.gz / Format: CCP4 / Size: 488.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpostprocess map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 504 pix.
= 429.005 Å		0.85 Å/pix.
x 504 pix.
= 429.005 Å		0.85 Å/pix.
x 504 pix.
= 429.005 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8512 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0095
Minimum - Maximum-0.0070644743 - 0.029554365
Average (Standard dev.)0.0003482867 (±0.0014684885)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions504504504
Spacing504504504
CellA=B=C: 429.0048 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_18214_msk_1.map
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Additional map: refinement map

Fileemd_18214_additional_1.map
Annotationrefinement map
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Half map: #2

Fileemd_18214_half_map_1.map
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Half map: #1

Fileemd_18214_half_map_2.map
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Sample components

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Entire : Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric as...

EntireName: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric assembly
Components
  • Complex: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric assembly
    • Protein or peptide: Cullin-9
    • Protein or peptide: E3 ubiquitin-protein ligase RBX1

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Supramolecule #1: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric as...

SupramoleculeName: Structure of CUL9-RBX1 ubiquitin E3 ligase complex - hexameric assembly
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cullin-9

MacromoleculeName: Cullin-9 / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 281.531875 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MVGERHAGDL MVPLGPRLQA YPEELIRQRP GHDGHPEYLI RWSVLKCGEV GKVGVEEGKA EHILMWLSAP EVYANCPGLL GERALSKGL QHEPAGVSGS FPRDPGGLDE VAMGEMEADV QALVRRAARQ LAESGTPSLT AAVLHTIHVL SAYASIGPLT G VFRETGAL ...String:
MVGERHAGDL MVPLGPRLQA YPEELIRQRP GHDGHPEYLI RWSVLKCGEV GKVGVEEGKA EHILMWLSAP EVYANCPGLL GERALSKGL QHEPAGVSGS FPRDPGGLDE VAMGEMEADV QALVRRAARQ LAESGTPSLT AAVLHTIHVL SAYASIGPLT G VFRETGAL DLLMHMLCNP EPQIRRSAGK MLQALAAHDA GSRAHVLLSL SQQDGIEQHM DFDSRYTLLE LFAETTSSEE HC MAFEGIH LPQIPGKLLF SLVKRYLCVT SLLDQLNSSP ELGAGDQSSP CATREKSRGQ RELEFSMAVG NLISELVRSM GWA RNLSEQ GMSPPRPTRS IFQPYISGPS LLLPTIVTTP RRQGWVFRQR SEFSSRSGYG EYVQQTLQPG MRVRMLDDYE EISA GDEGE FRQSNNGIPP VQVFWQSTGR TYWVHWHMLE ILGPEEATED KASAAVEKGA GATVLGTAFP SWDWNPMDGL YPLPY LQPE PQKNERVGYL TQAEWWELLF FIKKLDLCEQ QPIFQNLWKN LDETLGEKAL GEISVSVEMA ESLLQVLSSR FEGSTL NDL LNSQIYTKYG LLSNEPSSSS TSRNHSCTPD PEEESKSEAS FSEEETESLK AKAEAPKTEA EPTKTRTETP MAQSDSQ LF NQLLVTEGMT LPTEMKEAAS EMARALRGPG PRSSLDQHVA AVVATVQISS LDTNLQLSGL SALSQAVEEV TERDHPLV R PDRSLREKLV KMLVELLTNQ VGEKMVVVQA LRLLYLLMTK HEWRPLFARE GGIYAVLVCM QEYKTSVLVQ QAGLAALKM LAVASSSEIP TFVTGRDSIH SLFDAQMTRE IFASIDSATR PGSESLLLTV PAAVILMLNT EGCSSAARNG LLLLNLLLCN HHTLGDQII TQELRDTLFR HSGIAPRTEP MPTTRTILMM LLNRYSEPPG SPERAALETP IIQGQDGSPE LLIRSLVGGP S AELLLDLE RVLCREGSPG GAVRPLLKRL QQETQPFLLL LRTLDAPGPN KTLLLSVLRV ITRLLDFPEA MVLPWHEVLE PC LNCLSGP SSDSEIVQEL TCFLHRLASM HKDYAVVLCC LGAKEILSKV LDKHSAQLLL GCELRDLVTE CEKYAQLYSN LTS SILAGC IQMVLGQIED HRRTHQPINI PFFDVFLRHL CQGSSVEVKE DKCWEKVEVS SNPHRASKLT DHNPKTYWES NGST GSHYI TLHMHRGVLV RQLTLLVASE DSSYMPARVV VFGGDSTSCI GTELNTVNVM PSASRVILLE NLNRFWPIIQ IRIKR CQQG GIDTRVRGVE VLGPKPTFWP LFREQLCRRT CLFYTIRAQA WSRDIAEDHR RLLQLCPRLN RVLRHEQNFA DRFLPD DEA AQALGKTCWE ALVSPLVQNI TSPDAEGVSA LGWLLDQYLE QRETSRNPLS RAASFASRVR RLCHLLVHVE PPPGPSP EP STRPFSKNSK GRDRSPAPSP VLPSSSLRNI TQCWLSVVQE QVSRFLAAAW RAPDFVPRYC KLYEHLQRAG SELFGPRA A FMLALRSGFS GALLQQSFLT AAHMSEQFAR YIDQQIQGGL IGGAPGVEML GQLQRHLEPI MVLSGLELAT TFEHFYQHY MADRLLSFGS SWLEGAVLEQ IGLCFPNRLP QLMLQSLSTS EELQRQFHLF QLQRLDKLFL EQEDEEEKRL EEEEEEEEEE EAEKELFIE DPSPAISILV LSPRCWPVSP LCYLYHPRKC LPTEFCDALD RFSSFYSQSQ NHPVLDMGPH RRLQWTWLGR A ELQFGKQI LHVSTVQMWL LLKFNQTEEV SVETLLKDSD LSPELLLQAL VPLTSGNGPL TLHEGQDFPH GGVLRLHEPG PQ RSGEALW LIPPQAYLNV EKDEGRTLEQ KRNLLSCLLV RILKAHGEKG LHIDQLVCLV LEAWQKGPNP PGTLGHTVAG GVA CTSTDV LSCILHLLGQ GYVKRRDDRP QILMYAAPEP MGPCRGQADV PFCGSQSETS KPSPEAVATL ASLQLPAGRT MSPQ EVEGL MKQTVRQVQE TLNLEPDVAQ HLLAHSHWGA EQLLQSYSED PEPLLLAAGL CVHQAQAVPV RPDHCPVCVS PLGCD DDLP SLCCMHYCCK SCWNEYLTTR IEQNLVLNCT CPIADCPAQP TGAFIRAIVS SPEVISKYEK ALLRGYVESC SNLTWC TNP QGCDRILCRQ GLGCGTTCSK CGWASCFNCS FPEAHYPASC GHMSQWVDDG GYYDGMSVEA QSKHLAKLIS KRCPSCQ AP IEKNEGCLHM TCAKCNHGFC WRCLKSWKPN HKDYYNCSAM VSKAARQEKR FQDYNERCTF HHQAREFAVN LRNRVSAI H EVPPPRSFTF LNDACQGLEQ ARKVLAYACV YSFYSQDAEY MDVVEQQTEN LELHTNALQI LLEETLLRCR DLASSLRLL RADCLSTGME LLRRIQERLL AILQHSAQDF RVGLQSPSVE AWEAKGPNMP GSQPQASSGP EAEEEEEDDE DDVPEWQQDE FDEELDNDS FSYDESENLD QETFFFGDEE EDEDEAYD

UniProtKB: Cullin-9

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Macromolecule #2: E3 ubiquitin-protein ligase RBX1

MacromoleculeName: E3 ubiquitin-protein ligase RBX1 / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.289977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MAAAMDVDTP SGTNSGAGKK RFEVKKWNAV ALWAWDIVVD NCAICRNHIM DLCIECQANQ ASATSEECTV AWGVCNHAFH FHCISRWLK TRQVCPLDNR EWEFQKYGH

UniProtKB: E3 ubiquitin-protein ligase RBX1

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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

Concentration3 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 0.7000000000000001 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 611252
FSC plot (resolution estimation)

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