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- PDB-8h37: Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a tetrameric complex -

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Basic information

Entry
Database: PDB / ID: 8h37
TitleCryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a tetrameric complex
Components
  • Cullin-3
  • E3 ubiquitin-protein ligase RBX1
  • Kelch repeat and BTB domain-containing protein 2
  • Phosphatidylinositol 3-kinase regulatory subunit alpha
KeywordsLIGASE / complex
Function / homology
Function and homology information


positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / nuclear protein quality control by the ubiquitin-proteasome system / polar microtubule / regulation protein catabolic process at postsynapse / COPII vesicle coating ...positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / liver morphogenesis / POZ domain binding / perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / nuclear protein quality control by the ubiquitin-proteasome system / polar microtubule / regulation protein catabolic process at postsynapse / COPII vesicle coating / anaphase-promoting complex-dependent catabolic process / phosphatidylinositol kinase activity / positive regulation of focal adhesion disassembly / 1-phosphatidylinositol-3-kinase regulator activity / phosphatidylinositol 3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / T follicular helper cell differentiation / phosphatidylinositol 3-kinase complex / PI3K events in ERBB4 signaling / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / cullin-RING ubiquitin ligase complex / RHOBTB3 ATPase cycle / neurotrophin TRKA receptor binding / positive regulation of mitotic metaphase/anaphase transition / embryonic cleavage / Activated NTRK2 signals through PI3K / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / cis-Golgi network / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / cell projection organization / ErbB-3 class receptor binding / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Signaling by cytosolic FGFR1 fusion mutants / Co-stimulation by ICOS / positive regulation of protein autoubiquitination / RHOD GTPase cycle / RNA polymerase II transcription initiation surveillance / protein neddylation / phosphatidylinositol 3-kinase complex, class IA / Nephrin family interactions / RHOF GTPase cycle / kinase activator activity / Notch binding / Signaling by LTK in cancer / NEDD8 ligase activity / fibroblast apoptotic process / positive regulation of leukocyte migration / Signaling by LTK / MET activates PI3K/AKT signaling / VCB complex / RHOBTB1 GTPase cycle / PI3K/AKT activation / negative regulation of stress fiber assembly / RND1 GTPase cycle / positive regulation of filopodium assembly / negative regulation of response to oxidative stress / RND2 GTPase cycle / Cul5-RING ubiquitin ligase complex / RND3 GTPase cycle / growth hormone receptor signaling pathway / insulin binding / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / Signaling by ALK / stem cell division / ubiquitin-ubiquitin ligase activity / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / PI-3K cascade:FGFR3 / RHOV GTPase cycle / Cul4A-RING E3 ubiquitin ligase complex / RHOB GTPase cycle / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / Cul4-RING E3 ubiquitin ligase complex / mitotic metaphase chromosome alignment / Cul3-RING ubiquitin ligase complex / natural killer cell mediated cytotoxicity / GP1b-IX-V activation signalling / PI-3K cascade:FGFR2 / Cul4B-RING E3 ubiquitin ligase complex / stress fiber assembly / PI-3K cascade:FGFR4 / ubiquitin ligase complex scaffold activity / negative regulation of Rho protein signal transduction / negative regulation of mitophagy / PI-3K cascade:FGFR1 / Prolactin receptor signaling / positive regulation of cytokinesis / RHOC GTPase cycle / RHOJ GTPase cycle / intracellular glucose homeostasis
Similarity search - Function
Kelch repeat and BTB domain-containing protein 2 / : / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain ...Kelch repeat and BTB domain-containing protein 2 / : / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Zinc finger, RING-H2-type / RING-H2 zinc finger domain / BTB-kelch protein / Cullin protein neddylation domain / : / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Rho GTPase-activating protein domain / RhoGAP domain / Kelch motif / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Kelch / Kelch repeat type 1 / Cullin / Cullin, N-terminal / Cullin homology domain / Cullin homology domain superfamily / Cullin alpha solenoid domain / Cullin family profile. / Rho GTPase activation protein / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Zinc finger RING-type profile. / SH2 domain / Zinc finger, RING-type / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Zinc finger, RING/FYVE/PHD-type / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Phosphatidylinositol 3-kinase regulatory subunit alpha / E3 ubiquitin-protein ligase RBX1 / Cullin-3 / Kelch repeat and BTB domain-containing protein 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 7.52 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
C: Cullin-3
F: Cullin-3
M: Cullin-3
O: Cullin-3
E: E3 ubiquitin-protein ligase RBX1
D: E3 ubiquitin-protein ligase RBX1
R: E3 ubiquitin-protein ligase RBX1
Q: E3 ubiquitin-protein ligase RBX1
A: Kelch repeat and BTB domain-containing protein 2
G: Phosphatidylinositol 3-kinase regulatory subunit alpha
B: Kelch repeat and BTB domain-containing protein 2
H: Phosphatidylinositol 3-kinase regulatory subunit alpha
I: Phosphatidylinositol 3-kinase regulatory subunit alpha
N: Kelch repeat and BTB domain-containing protein 2
J: Phosphatidylinositol 3-kinase regulatory subunit alpha
P: Kelch repeat and BTB domain-containing protein 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)1,026,76528
Polymers1,025,98016
Non-polymers78512
Water00
1


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

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Components

#1: Protein
Cullin-3 / CUL-3


Mass: 89063.328 Da / Num. of mol.: 4
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
#2: 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.: 4
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
#3: Protein
Kelch repeat and BTB domain-containing protein 2 / BTB and kelch domain-containing protein 1


Mass: 71431.375 Da / Num. of mol.: 4 / Mutation: S252D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KBTBD2, BKLHD1, KIAA1489, CGI-73 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q8IY47
#4: Protein
Phosphatidylinositol 3-kinase regulatory subunit alpha / PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory ...PI3-kinase regulatory subunit alpha / PI3K regulatory subunit alpha / PtdIns-3-kinase regulatory subunit alpha / Phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha / PI3-kinase subunit p85-alpha / PtdIns-3-kinase regulatory subunit p85-alpha


Mass: 83710.281 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PIK3R1, GRB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P27986
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
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

ComponentName: KBTBD2-CUL3-Rbx1-p85a tetrameric complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 45 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: 7.52 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 239068 / Symmetry type: POINT

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