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- PDB-8h38: Cryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate) complex -

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Basic information

Entry
Database: PDB / ID: 8h38
TitleCryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate) complex
Components
  • (COP9 signalosome complex subunit ...) x 8
  • Cullin-3
  • E3 ubiquitin-protein ligase RBX1
  • Kelch repeat and BTB domain-containing protein 2
  • NEDD8
KeywordsLIGASE / complex
Function / homology
Function and homology information


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 / liver morphogenesis / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / POZ domain binding / regulation of IRE1-mediated unfolded protein response / exosomal secretion ...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 / liver morphogenesis / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / POZ domain binding / regulation of IRE1-mediated unfolded protein response / exosomal secretion / deNEDDylase activity / GTPase inhibitor activity / nuclear protein quality control by the ubiquitin-proteasome system / regulation protein catabolic process at postsynapse / polar microtubule / regulation of protein neddylation / protein deneddylation / eukaryotic translation initiation factor 3 complex / activation of NF-kappaB-inducing kinase activity / anaphase-promoting complex-dependent catabolic process / COPII vesicle coating / stem cell division / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / embryonic cleavage / cell projection organization / COP9 signalosome / Cul7-RING ubiquitin ligase complex / positive regulation of mitotic metaphase/anaphase transition / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / regulation of proteolysis / positive regulation of protein autoubiquitination / protein neddylation / metal-dependent deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases) / NEDD8 ligase activity / Notch binding / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / RHOBTB1 GTPase cycle / fibroblast apoptotic process / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / SCF ubiquitin ligase complex / inner cell mass cell proliferation / negative regulation of Rho protein signal transduction / Cul2-RING ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Cul4B-RING E3 ubiquitin ligase complex / negative regulation of type I interferon production / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / mitotic metaphase chromosome alignment / Cul3-RING ubiquitin ligase complex / stress fiber assembly / Prolactin receptor signaling / skeletal muscle cell differentiation / protein monoubiquitination / positive regulation of cytokinesis / TGF-beta receptor signaling activates SMADs / cullin family protein binding / regulation of JNK cascade / ubiquitin-like ligase-substrate adaptor activity / response to light stimulus / sperm flagellum / anatomical structure morphogenesis / protein K48-linked ubiquitination / RHOBTB2 GTPase cycle / protein autoubiquitination / endoplasmic reticulum to Golgi vesicle-mediated transport / Nuclear events stimulated by ALK signaling in cancer / JNK cascade / gastrulation / positive regulation of TORC1 signaling / T cell activation / translation initiation factor activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of cellular response to insulin stimulus / Regulation of BACH1 activity / intrinsic apoptotic signaling pathway / cyclin binding / post-translational protein modification / positive regulation of protein ubiquitination / integrin-mediated signaling pathway / Degradation of DVL / Recognition of DNA damage by PCNA-containing replication complex / Degradation of GLI1 by the proteasome / Negative regulation of NOTCH4 signaling / cellular response to amino acid stimulus / Iron uptake and transport / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Vif-mediated degradation of APOBEC3G / Hedgehog 'on' state / 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 / DNA Damage Recognition in GG-NER
Similarity search - Function
Kelch repeat and BTB domain-containing protein 2 / : / 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 ...Kelch repeat and BTB domain-containing protein 2 / : / 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 / Nedd8-like ubiquitin / Eukaryotic translation initiation factor 3 subunit M eIF3m/COP9 signalosome complex subunit 7 COPS7 / 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 / BTB-kelch protein / PCI/PINT associated module / BTB/Kelch-associated / BTB And C-terminal Kelch / Cullin protein neddylation domain / BTB And C-terminal Kelch / : / Cullin, conserved site / Cullin family signature. / Cullin / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin protein neddylation domain / Kelch / CSN8/PSMD8/EIF3K / CSN8/PSMD8/EIF3K family / Kelch repeat type 1 / Rpn11/EIF3F, C-terminal / Kelch motif / Maintenance of mitochondrial structure and function / : / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin family / Cullin family profile. / motif in proteasome subunits, Int-6, Nip-1 and TRIP-15 / PCI domain / Proteasome component (PCI) domain / PCI domain profile. / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / JAB1/Mov34/MPN/PAD-1 ubiquitin protease / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / JAB/MPN domain / JAB1/MPN/MOV34 metalloenzyme domain / SKP1/BTB/POZ domain superfamily / MPN domain / MPN domain profile. / Zinc finger RING-type profile. / Zinc finger, RING-type / : / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Tetratricopeptide-like helical domain superfamily / 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
COP9 signalosome complex subunit 2 / E3 ubiquitin-protein ligase RBX1 / COP9 signalosome complex subunit 1 / Cullin-3 / NEDD8 / COP9 signalosome complex subunit 6 / Kelch repeat and BTB domain-containing protein 2 / COP9 signalosome complex subunit 5 / COP9 signalosome complex subunit 8 / COP9 signalosome complex subunit 4 ...COP9 signalosome complex subunit 2 / E3 ubiquitin-protein ligase RBX1 / COP9 signalosome complex subunit 1 / Cullin-3 / NEDD8 / COP9 signalosome complex subunit 6 / Kelch repeat and BTB domain-containing protein 2 / 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 / Resolution: 4.25 Å
AuthorsHu, Y. / Mao, Q. / Chen, Z. / Sun, L.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81900729 China
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Dynamic molecular architecture and substrate recruitment of cullin3-RING E3 ligase CRL3.
Authors: Yuxia Hu / Zhao Zhang / Qiyu Mao / Xiang Zhang / Aihua Hao / Yu Xun / Yeda Wang / Lin Han / Wuqiang Zhan / Qianying Liu / Yue Yin / Chao Peng / Eva Marie Y Moresco / Zhenguo Chen / Bruce Beutler / Lei Sun /
Abstract: Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. ...Phosphatidylinositol 3-kinase α, a heterodimer of catalytic p110α and one of five regulatory subunits, mediates insulin- and insulin like growth factor-signaling and, frequently, oncogenesis. Cellular levels of the regulatory p85α subunit are tightly controlled by regulated proteasomal degradation. In adipose tissue and growth plates, failure of K48-linked p85α ubiquitination causes diabetes, lipodystrophy and dwarfism in mice, as in humans with SHORT syndrome. Here we elucidated the structures of the key ubiquitin ligase complexes regulating p85α availability. Specificity is provided by the substrate receptor KBTBD2, which recruits p85α to the cullin3-RING E3 ubiquitin ligase (CRL3). CRL3 forms multimers, which disassemble into dimers upon substrate binding (CRL3-p85α) and/or neddylation by the activator NEDD8 (CRL3~N8), leading to p85α ubiquitination and degradation. Deactivation involves dissociation of NEDD8 mediated by the COP9 signalosome and displacement of KBTBD2 by the inhibitor CAND1. The hereby identified structural basis of p85α regulation opens the way to better understanding disturbances of glucose regulation, growth and cancer.
History
DepositionOct 8, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
G: COP9 signalosome complex subunit 7b
H: COP9 signalosome complex subunit 8
I: Kelch repeat and BTB domain-containing protein 2
L: Cullin-3
M: Kelch repeat and BTB domain-containing protein 2
R: E3 ubiquitin-protein ligase RBX1
N: NEDD8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)584,69017
Polymers584,42813
Non-polymers2624
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein COP9 signalosome complex subunit 1 / SGN1 / Signalosome subunit 1 / G protein pathway suppressor 1 / GPS-1 / JAB1-containing signalosome ...SGN1 / Signalosome subunit 1 / G protein pathway suppressor 1 / GPS-1 / JAB1-containing signalosome subunit 1 / Protein MFH


Mass: 59122.176 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPS1, COPS1, CSN1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13098
#2: Protein COP9 signalosome complex subunit 2 / SGN2 / Signalosome subunit 2 / Alien homolog / JAB1-containing signalosome subunit 2 / Thyroid ...SGN2 / Signalosome subunit 2 / Alien homolog / JAB1-containing signalosome subunit 2 / Thyroid receptor-interacting protein 15 / TR-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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P61201
#3: Protein COP9 signalosome complex subunit 3 / SGN3 / Signalosome subunit 3 / JAB1-containing signalosome subunit 3


Mass: 47924.008 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS3, CSN3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9UNS2
#4: Protein COP9 signalosome complex subunit 4 / SGN4 / 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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9BT78
#5: Protein COP9 signalosome complex subunit 5 / SGN5 / Signalosome subunit 5 / Jun activation domain-binding protein 1


Mass: 37554.672 Da / Num. of mol.: 1 / Mutation: H138A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS5, CSN5, JAB1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: Q92905, Hydrolases; Acting on peptide bonds (peptidases)
#6: Protein COP9 signalosome complex subunit 6 / SGN6 / Signalosome subunit 6 / JAB1-containing signalosome subunit 6 / MOV34 homolog / Vpr- ...SGN6 / Signalosome subunit 6 / JAB1-containing signalosome subunit 6 / MOV34 homolog / Vpr-interacting protein / hVIP


Mass: 36203.398 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS6, CSN6, HVIP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q7L5N1
#7: Protein COP9 signalosome complex subunit 7b / SGN7b / Signalosome subunit 7b / JAB1-containing signalosome subunit 7b


Mass: 29656.928 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: COPS7B, CSN7B / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H9Q2
#8: Protein COP9 signalosome complex subunit 8 / SGN8 / 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 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q99627

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Protein , 4 types, 5 molecules IMLRN

#9: Protein Kelch repeat and BTB domain-containing protein 2


Mass: 71403.367 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8IY47
#10: Protein Cullin-3 / CUL-3


Mass: 89063.328 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CUL3, KIAA0617 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q13618
#11: Protein E3 ubiquitin-protein ligase RBX1 / E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / ...E3 ubiquitin-protein transferase RBX1 / Protein ZYP / RING finger protein 75 / RING-box protein 1 / Rbx1 / Regulator of cullins 1 / ROC1


Mass: 12289.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RBX1, RNF75, ROC1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase
#12: Protein NEDD8 / Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / ...Neddylin / Neural precursor cell expressed developmentally down-regulated protein 8 / NEDD-8 / Ubiquitin-like protein Nedd8


Mass: 8573.978 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NEDD8 / Production host: Escherichia coli (E. coli) / References: UniProt: Q15843

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Non-polymers , 1 types, 4 molecules

#13: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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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

Component
IDNameTypeEntity IDParent-IDSource
1KBTBD2-CRL3~N8 dimer assemble with CSN(mutate) monomerCOMPLEX#1-#120RECOMBINANT
2CSN subunit1, KBTBD2, CUllin-3, Rbx1COMPLEX#1, #9-#111RECOMBINANT
3CSNCOMPLEX#2-#81RECOMBINANT
4NEDD8COMPLEX#121RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Trichoplusia ni (cabbage looper)7111
34Escherichia coli (E. coli)562
Buffer solutionpH: 7.8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: NO

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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 FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 53 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 146505 / Symmetry type: POINT

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