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Basic information
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Title | Cryo-EM Structure of the KBTBD2-CRL3~N8-CSN(mutate) complex | |||||||||
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![]() | ligase / complex | |||||||||
Function / homology | ![]() 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 / nuclear protein quality control by the ubiquitin-proteasome system / deNEDDylase activity / GTPase inhibitor activity / regulation protein catabolic process at postsynapse / polar microtubule / regulation of protein neddylation / eukaryotic translation initiation factor 3 complex / protein deneddylation / anaphase-promoting complex-dependent catabolic process / COPII vesicle coating / cullin-RING-type E3 NEDD8 transferase / stem cell division / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / embryonic cleavage / cell projection organization / COP9 signalosome / positive regulation of mitotic metaphase/anaphase transition / Cul7-RING ubiquitin ligase complex / 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 / regulation of proteolysis / positive regulation of protein autoubiquitination / protein neddylation / metal-dependent deubiquitinase activity / Hydrolases; Acting on peptide bonds (peptidases) / Notch binding / NEDD8 ligase activity / RHOBTB1 GTPase cycle / Cul5-RING ubiquitin ligase complex / negative regulation of response to oxidative stress / ubiquitin-ubiquitin ligase activity / fibroblast apoptotic process / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of Rho protein signal transduction / SCF ubiquitin ligase complex / inner cell mass cell proliferation / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / mitotic metaphase chromosome alignment / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / stress fiber assembly / protein deubiquitination / Prolactin receptor signaling / skeletal muscle cell differentiation / positive regulation of cytokinesis / TGF-beta receptor signaling activates SMADs / protein monoubiquitination / cullin family protein binding / regulation of JNK cascade / response to light stimulus / sperm flagellum / anatomical structure morphogenesis / protein autoubiquitination / RHOBTB2 GTPase cycle / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / endoplasmic reticulum to Golgi vesicle-mediated transport / gastrulation / JNK cascade / positive regulation of TORC1 signaling / T cell activation / translation initiation factor activity / Regulation of BACH1 activity / cyclin binding / intrinsic apoptotic signaling pathway / phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / Iron uptake and transport / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / cellular response to amino acid stimulus / 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 / protein destabilization Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / Resolution: 4.25 Å | |||||||||
![]() | Hu Y / Mao Q / Chen Z / Sun L | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 34.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 32.5 KB 32.5 KB | Display Display | ![]() |
Images | ![]() | 99.9 KB | ||
Filedesc metadata | ![]() | 9.1 KB | ||
Others | ![]() ![]() | 29.7 MB 29.7 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 616.1 KB | Display | ![]() |
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Full document | ![]() | 615.7 KB | Display | |
Data in XML | ![]() | 10.9 KB | Display | |
Data in CIF | ![]() | 12.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8h38MC ![]() 8gq6C ![]() 8h33C ![]() 8h34C ![]() 8h35C ![]() 8h36C ![]() 8h37C ![]() 8h3aC ![]() 8h3fC ![]() 8h3qC ![]() 8h3rC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 2.088 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34455_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34455_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
+Entire : KBTBD2-CRL3~N8 dimer assemble with CSN(mutate) monomer
+Supramolecule #1: KBTBD2-CRL3~N8 dimer assemble with CSN(mutate) monomer
+Supramolecule #2: CSN subunit1, KBTBD2, CUllin-3, Rbx1
+Supramolecule #3: CSN
+Supramolecule #4: NEDD8
+Macromolecule #1: COP9 signalosome complex subunit 1
+Macromolecule #2: COP9 signalosome complex subunit 2
+Macromolecule #3: COP9 signalosome complex subunit 3
+Macromolecule #4: COP9 signalosome complex subunit 4
+Macromolecule #5: COP9 signalosome complex subunit 5
+Macromolecule #6: COP9 signalosome complex subunit 6
+Macromolecule #7: COP9 signalosome complex subunit 7b
+Macromolecule #8: COP9 signalosome complex subunit 8
+Macromolecule #9: Kelch repeat and BTB domain-containing protein 2
+Macromolecule #10: Cullin-3
+Macromolecule #11: E3 ubiquitin-protein ligase RBX1
+Macromolecule #12: NEDD8
+Macromolecule #13: ZINC ION
-Experimental details
-Structure determination
![]() | single particle reconstruction |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.8 |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 53.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: Details: 6r7f |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.25 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 146505 |
Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: PROJECTION MATCHING |