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- PDB-6r6h: Structural basis of Cullin-2 RING E3 ligase regulation by the COP... -

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Entry
Database: PDB / ID: 6r6h
TitleStructural basis of Cullin-2 RING E3 ligase regulation by the COP9 signalosome
Components
  • (COP9 signalosome complex subunit ...) x 8
  • Cullin-2CUL2
  • ELOC_HUMAN
  • Elongin-B
  • RBX1_HUMAN
  • von Hippel-Lindau disease tumor suppressor
KeywordsLIGASE / Cullin-Ring E3 Ligase COP9 Signalosome Neddylation
Function / homology
Function and homology information


nucleotide-excision repair factor 4 complex / regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / COP9 signalosome assembly / trophectodermal cell proliferation / macrophage migration inhibitory factor binding / global genome nucleotide-excision repair / regulation of IRE1-mediated unfolded protein response / exosomal secretion / deNEDDylase activity / GTPase inhibitor activity ...nucleotide-excision repair factor 4 complex / regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / COP9 signalosome assembly / trophectodermal cell proliferation / macrophage migration inhibitory factor binding / global genome nucleotide-excision repair / regulation of IRE1-mediated unfolded protein response / exosomal secretion / deNEDDylase activity / GTPase inhibitor activity / eukaryotic translation initiation factor 3 complex / regulation of protein neddylation / protein deneddylation / regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / COP9 signalosome / Cul7-RING ubiquitin ligase complex / metal-dependent deubiquitinase activity / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / activation of NF-kappaB-inducing kinase activity / 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 / Hydrolases; Acting on peptide bonds (peptidases) / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / RHOBTB1 GTPase cycle / 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 / inner cell mass cell proliferation / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul3-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / TP53 Regulates Transcription of DNA Repair Genes / SUMOylation of ubiquitinylation proteins / Prolactin receptor signaling / protein deubiquitination / negative regulation of transcription elongation by RNA polymerase II / skeletal muscle cell differentiation / protein monoubiquitination / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / regulation of JNK cascade / response to light stimulus / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / ubiquitin-like ligase-substrate adaptor activity / 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 / negative regulation of signal transduction / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / response to UV / JNK cascade / negative regulation of TORC1 signaling / positive regulation of TORC1 signaling / RNA Polymerase II Pre-transcription Events / translation initiation factor activity / Regulation of BACH1 activity / T cell activation / post-translational protein modification / intrinsic apoptotic signaling pathway / negative regulation of autophagy / 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 / nucleotide-excision repair / positive regulation of cell differentiation / 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 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / G1/S transition of mitotic cell cycle
Similarity search - Function
COP9 signalosome, subunit CSN8 / COP9 signalosome complex subunit 7, helix I / : / : / COP9 signalosome complex subunit 7a helix I domain / COP9 signalosome complex subunit 1, C-terminal helix / COP9 signalosome complex subunit 3-like, C-terminal helix / COP9 signalosome subunit 6 / Cop9 signalosome subunit 5 C-terminal domain / COP9 signalosome complex subunit 4, helix turn helix domain ...COP9 signalosome, subunit CSN8 / COP9 signalosome complex subunit 7, helix I / : / : / COP9 signalosome complex subunit 7a helix I domain / COP9 signalosome complex subunit 1, C-terminal helix / COP9 signalosome complex subunit 3-like, C-terminal helix / COP9 signalosome subunit 6 / Cop9 signalosome subunit 5 C-terminal domain / COP9 signalosome complex subunit 4, helix turn helix domain / Cop9 signalosome subunit 5 C-terminal domain / CSN4/RPN5/eIF3a helix turn helix domain / Eukaryotic translation initiation factor 3 subunit M eIF3m/COP9 signalosome complex subunit 7 COPS7 / von Hippel-Lindau disease tumour suppressor, beta/alpha domain / von Hippel-Lindau disease tumour suppressor, alpha domain / von Hippel-Lindau disease tumour suppressor, beta domain / VHL superfamily / von Hippel-Lindau disease tumour suppressor, alpha domain superfamily / von Hippel-Lindau disease tumour suppressor, beta domain superfamily / VHL beta domain / VHL box domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / 26S proteasome regulatory subunit Rpn7, N-terminal / 26S proteasome regulatory subunit Rpn7/COP9 signalosome complex subunit 1 / 26S proteasome subunit RPN7 / 26S Proteasome non-ATPase regulatory subunit 12/COP9 signalosome complex subunit 4 / PCI/PINT associated module / 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 / CSN8/PSMD8/EIF3K / CSN8/PSMD8/EIF3K family / Rpn11/EIF3F, C-terminal / Maintenance of mitochondrial structure and function / Cullin / motif in proteasome subunits, Int-6, Nip-1 and TRIP-15 / PCI domain / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / Proteasome component (PCI) domain / PCI domain profile. / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / MPN domain / MPN domain profile. / SKP1/BTB/POZ domain superfamily / 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
von Hippel-Lindau disease tumor suppressor / COP9 signalosome complex subunit 2 / E3 ubiquitin-protein ligase RBX1 / Elongin-C / COP9 signalosome complex subunit 1 / Cullin-2 / Elongin-B / COP9 signalosome complex subunit 6 / COP9 signalosome complex subunit 5 / COP9 signalosome complex subunit 8 ...von Hippel-Lindau disease tumor suppressor / COP9 signalosome complex subunit 2 / E3 ubiquitin-protein ligase RBX1 / Elongin-C / COP9 signalosome complex subunit 1 / Cullin-2 / Elongin-B / COP9 signalosome complex subunit 6 / COP9 signalosome complex subunit 5 / COP9 signalosome complex subunit 8 / COP9 signalosome complex subunit 4 / COP9 signalosome complex subunit 7b / COP9 signalosome complex subunit 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 8.4 Å
AuthorsMorris, E.P. / Faull, S.V. / Lau, A.M.C. / Politis, A. / Beuron, F. / Cronin, N.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
CitationJournal: Nat Commun / Year: 2019
Title: Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome.
Authors: Sarah V Faull / Andy M C Lau / Chloe Martens / Zainab Ahdash / Kjetil Hansen / Hugo Yebenes / Carla Schmidt / Fabienne Beuron / Nora B Cronin / Edward P Morris / Argyris Politis /
Abstract: Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. ...Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.
History
DepositionMar 27, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 28, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 4, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title

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Assembly

Deposited unit
A: COP9 signalosome complex subunit 1
B: COP9 signalosome complex subunit 2
C: COP9 signalosome complex subunit 3
D: COP9 signalosome complex subunit 4
E: COP9 signalosome complex subunit 5
F: COP9 signalosome complex subunit 6
H: COP9 signalosome complex subunit 8
O: Cullin-2
P: Elongin-B
Q: ELOC_HUMAN
R: RBX1_HUMAN
V: von Hippel-Lindau disease tumor suppressor
G: COP9 signalosome complex subunit 7b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)455,95814
Polymers455,89313
Non-polymers651
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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COP9 signalosome complex subunit ... , 8 types, 8 molecules ABCDEFHG

#1: Protein COP9 signalosome complex subunit 1 / / Signalosome subunit 1 / G protein pathway suppressor 1 / GPS-1 / JAB1-containing signalosome ...Signalosome subunit 1 / G protein pathway suppressor 1 / GPS-1 / JAB1-containing signalosome subunit 1 / Protein MFH


Mass: 55606.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPS1, COPS1, CSN1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13098
#2: Protein COP9 signalosome complex subunit 2 / / Signalosome subunit 2 / Alien homolog / JAB1-containing signalosome subunit 2 / Thyroid receptor- ...Signalosome subunit 2 / Alien homolog / JAB1-containing signalosome subunit 2 / Thyroid receptor-interacting protein 15 / TRIP-15


Mass: 51664.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS2, CSN2, TRIP15 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P61201
#3: Protein COP9 signalosome complex subunit 3 / / Signalosome subunit 3 / JAB1-containing signalosome subunit 3


Mass: 45808.816 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS3, CSN3 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UNS2
#4: Protein COP9 signalosome complex subunit 4 / / Signalosome subunit 4 / JAB1-containing signalosome subunit 4


Mass: 46322.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS4, CSN4 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BT78
#5: Protein COP9 signalosome complex subunit 5 / / Signalosome subunit 5 / Jun activation domain-binding protein 1


Mass: 37621.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS5, CSN5, JAB1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q92905, Hydrolases; Acting on peptide bonds (peptidases)
#6: Protein COP9 signalosome complex subunit 6 / / Signalosome subunit 6 / JAB1-containing signalosome subunit 6 / MOV34 homolog / Vpr-interacting protein / hVIP


Mass: 34713.844 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS6, CSN6, HVIP / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q7L5N1
#7: Protein COP9 signalosome complex subunit 8 / / Signalosome subunit 8 / COP9 homolog / hCOP9 / JAB1-containing signalosome subunit 8


Mass: 23245.543 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS8, CSN8 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q99627
#13: Protein COP9 signalosome complex subunit 7b / / Signalosome subunit 7b / JAB1-containing signalosome subunit 7b


Mass: 23228.529 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS7B, CSN7B / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9H9Q2

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Protein , 5 types, 5 molecules OPQRV

#8: Protein Cullin-2 / CUL2 / CUL-2


Mass: 87098.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13617
#9: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 11819.483 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q15370
#10: Protein ELOC_HUMAN


Mass: 11338.760 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q03071*PLUS
#11: Protein RBX1_HUMAN


Mass: 10092.631 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62877*PLUS
#12: Protein von Hippel-Lindau disease tumor suppressor / Protein G7 / pVHL


Mass: 17330.764 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VHL / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P40337

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Non-polymers , 1 types, 1 molecules

#14: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cullin-Ring E3 Ligases (CRLs) complexes with neddylated COP9 signalosome (CSN)
Type: COMPLEX / Entity ID: #1-#13 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: sf9
Buffer solutionpH: 7.5
Details: 15 mM Hepes pH 7.5 100 mM NaCl 0.5 mM DTT 1% glycerol
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: NITROGEN

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 47170 X / Nominal defocus max: 3000 nm / Nominal defocus min: 1800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 45 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 30 eV

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 8.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 24040 / Symmetry type: POINT

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