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- PDB-8h36: Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a dimeric complex -

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Basic information

Entry
Database: PDB / ID: 8h36
TitleCryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a dimeric 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 / polar microtubule / nuclear protein quality control by the ubiquitin-proteasome system / COPII vesicle coating / regulation protein catabolic process at postsynapse ...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 / polar microtubule / nuclear protein quality control by the ubiquitin-proteasome system / COPII vesicle coating / regulation protein catabolic process at postsynapse / anaphase-promoting complex-dependent catabolic process / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / 1-phosphatidylinositol-3-kinase regulator activity / positive regulation of endoplasmic reticulum unfolded protein response / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / T follicular helper cell differentiation / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / phosphatidylinositol 3-kinase regulatory subunit binding / myeloid leukocyte migration / negative regulation of beige fat cell differentiation / neurotrophin TRKA receptor binding / positive regulation of focal adhesion disassembly / RHOBTB3 ATPase cycle / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / Activated NTRK2 signals through PI3K / embryonic cleavage / cis-Golgi network / transmembrane receptor protein tyrosine kinase adaptor activity / Activated NTRK3 signals through PI3K / cullin-RING ubiquitin ligase complex / ErbB-3 class receptor binding / phosphatidylinositol 3-kinase complex / negative regulation of stress fiber assembly / Cul7-RING ubiquitin ligase complex / cellular response to chemical stress / Signaling by cytosolic FGFR1 fusion mutants / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Co-stimulation by ICOS / protein K27-linked ubiquitination / RHOD GTPase cycle / positive regulation of mitotic metaphase/anaphase transition / positive regulation of protein autoubiquitination / Nephrin family interactions / RNA polymerase II transcription initiation surveillance / Notch binding / protein neddylation / fibroblast apoptotic process / cell projection organization / Signaling by LTK in cancer / RHOF GTPase cycle / Signaling by LTK / kinase activator activity / positive regulation of leukocyte migration / MET activates PI3K/AKT signaling / RND1 GTPase cycle / PI3K/AKT activation / phosphatidylinositol 3-kinase complex, class IA / RND2 GTPase cycle / NEDD8 ligase activity / RND3 GTPase cycle / positive regulation of filopodium assembly / negative regulation of Rho protein signal transduction / RHOBTB1 GTPase cycle / growth hormone receptor signaling pathway / insulin binding / negative regulation of response to oxidative stress / VCB complex / Signaling by ALK / Cul5-RING ubiquitin ligase complex / RHOV GTPase cycle / ubiquitin-ubiquitin ligase activity / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / RHOB GTPase cycle / natural killer cell mediated cytotoxicity / GP1b-IX-V activation signalling / stem cell division / SCF ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / mitotic metaphase chromosome alignment / negative regulation of type I interferon production / Cul2-RING ubiquitin ligase complex / PI-3K cascade:FGFR2 / Cul3-RING ubiquitin ligase complex / PI-3K cascade:FGFR4 / stress fiber assembly / PI-3K cascade:FGFR1 / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / negative regulation of mitophagy / positive regulation of cytokinesis / RHOC GTPase cycle / Cul4A-RING E3 ubiquitin ligase complex / Cul4-RING E3 ubiquitin ligase complex / RHOJ GTPase cycle / Prolactin receptor signaling / negative regulation of osteoclast differentiation
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 / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / : / Cullin alpha+beta domain / Cullin protein neddylation domain / : / Kelch repeat type 1 / Cullin, conserved site / Cullin family signature. / Cullin repeat-like-containing domain superfamily / Cullin protein, neddylation domain / Cullin / Cullin protein neddylation domain / Cullin, N-terminal / Cullin alpha solenoid domain / Cullin / Cullin homology domain / Cullin homology domain superfamily / 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 / SH2 domain / Src homology 3 domains / Zinc finger RING-type profile. / SH2 domain superfamily / Zinc finger, RING-type / 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: 4.6 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

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Assembly

Deposited unit
E: E3 ubiquitin-protein ligase RBX1
A: Kelch repeat and BTB domain-containing protein 2
G: Phosphatidylinositol 3-kinase regulatory subunit alpha
C: Cullin-3
B: Kelch repeat and BTB domain-containing protein 2
H: Phosphatidylinositol 3-kinase regulatory subunit alpha
F: Cullin-3
D: E3 ubiquitin-protein ligase RBX1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)513,38214
Polymers512,9908
Non-polymers3926
Water00
1


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

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Components

#1: 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.: 2
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
#2: Protein Kelch repeat and BTB domain-containing protein 2 / BTB and kelch domain-containing protein 1


Mass: 71431.375 Da / Num. of mol.: 2 / 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
#3: 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.: 2
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
#4: Protein Cullin-3 / CUL-3


Mass: 89063.328 Da / Num. of mol.: 2
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
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 6 / 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 dimeric 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: 7.8
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: 4.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 333476 / Symmetry type: POINT

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