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Yorodumi- EMDB-34453: Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a tetrameric complex -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-34453 | |||||||||
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Title | Cryo-EM Structure of the KBTBD2-CUL3-Rbx1-p85a tetrameric complex | |||||||||
Map data | ||||||||||
Sample |
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Keywords | ligase / complex | |||||||||
Function / homology | Function and homology information liver morphogenesis / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / POZ domain binding / nuclear protein quality control by the ubiquitin-proteasome system / regulation protein catabolic process at postsynapse / perinuclear endoplasmic reticulum membrane / polar microtubule / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity ...liver morphogenesis / positive regulation of mitotic cell cycle phase transition / trophectodermal cellular morphogenesis / POZ domain binding / nuclear protein quality control by the ubiquitin-proteasome system / regulation protein catabolic process at postsynapse / perinuclear endoplasmic reticulum membrane / polar microtubule / regulation of toll-like receptor 4 signaling pathway / phosphatidylinositol kinase activity / anaphase-promoting complex-dependent catabolic process / phosphatidylinositol 3-kinase regulator activity / COPII vesicle coating / cullin-RING-type E3 NEDD8 transferase / stem cell division / positive regulation of focal adhesion disassembly / IRS-mediated signalling / phosphatidylinositol 3-kinase activator activity / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / interleukin-18-mediated signaling pathway / cullin-RING ubiquitin ligase complex / PI3K events in ERBB4 signaling / myeloid leukocyte migration / embryonic cleavage / 1-phosphatidylinositol-3-kinase regulator activity / cell projection organization / positive regulation of mitotic metaphase/anaphase transition / Cul7-RING ubiquitin ligase complex / phosphatidylinositol 3-kinase regulatory subunit binding / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / Activated NTRK3 signals through PI3K / cis-Golgi network / ErbB-3 class receptor binding / kinase activator activity / RHOF GTPase cycle / positive regulation of protein autoubiquitination / transmembrane receptor protein tyrosine kinase adaptor activity / RHOD GTPase cycle / protein neddylation / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / Notch binding / NEDD8 ligase activity / RHOBTB1 GTPase cycle / RND1 GTPase cycle / Cul5-RING ubiquitin ligase complex / Costimulation by the CD28 family / negative regulation of response to oxidative stress / positive regulation of leukocyte migration / MET activates PI3K/AKT signaling / RND2 GTPase cycle / ubiquitin-ubiquitin ligase activity / fibroblast apoptotic process / PI3K/AKT activation / positive regulation of filopodium assembly / RND3 GTPase cycle / negative regulation of stress fiber assembly / Cul4A-RING E3 ubiquitin ligase complex / growth hormone receptor signaling pathway / SCF ubiquitin ligase complex / negative regulation of Rho protein signal transduction / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / insulin binding / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / RHOV GTPase cycle / mitotic metaphase chromosome alignment / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / negative regulation of cell-matrix adhesion / Signaling by ALK / RHOB GTPase cycle / GP1b-IX-V activation signalling / PI-3K cascade:FGFR3 / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / stress fiber assembly / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / Prolactin receptor signaling / RHOC GTPase cycle / PI-3K cascade:FGFR1 / negative regulation of osteoclast differentiation / positive regulation of cytokinesis / intracellular glucose homeostasis / protein monoubiquitination / CD28 dependent PI3K/Akt signaling / Synthesis of PIPs at the plasma membrane / cullin family protein binding / phosphatidylinositol phosphate biosynthetic process Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 7.52 Å | |||||||||
Authors | Hu Y / Mao Q / Chen Z / Sun L | |||||||||
Funding support | China, 1 items
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Citation | Journal: 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 |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_34453.map.gz | 24 MB | EMDB map data format | |
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Header (meta data) | emd-34453-v30.xml emd-34453.xml | 19.8 KB 19.8 KB | Display Display | EMDB header |
Images | emd_34453.png | 80.8 KB | ||
Filedesc metadata | emd-34453.cif.gz | 7.2 KB | ||
Others | emd_34453_half_map_1.map.gz emd_34453_half_map_2.map.gz | 20.6 MB 20.6 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-34453 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-34453 | HTTPS FTP |
-Validation report
Summary document | emd_34453_validation.pdf.gz | 584.7 KB | Display | EMDB validaton report |
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Full document | emd_34453_full_validation.pdf.gz | 584.3 KB | Display | |
Data in XML | emd_34453_validation.xml.gz | 10.4 KB | Display | |
Data in CIF | emd_34453_validation.cif.gz | 12.2 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34453 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-34453 | HTTPS FTP |
-Related structure data
Related structure data | 8h37MC 8gq6C 8h33C 8h34C 8h35C 8h36C 8h38C 8h3aC 8h3fC 8h3qC 8h3rC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_34453.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 2.664 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_34453_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #1
File | emd_34453_half_map_2.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Sample components
-Entire : KBTBD2-CUL3-Rbx1-p85a tetrameric complex
Entire | Name: KBTBD2-CUL3-Rbx1-p85a tetrameric complex |
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Components |
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-Supramolecule #1: KBTBD2-CUL3-Rbx1-p85a tetrameric complex
Supramolecule | Name: KBTBD2-CUL3-Rbx1-p85a tetrameric complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: Homo sapiens (human) |
-Macromolecule #1: Cullin-3
Macromolecule | Name: Cullin-3 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 89.063328 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN AYTMVLHKHG EKLYTGLREV VTEHLINKV REDVLNSLNN NFLQTLNQAW NDHQTAMVMI RDILMYMDRV YVQQNNVENV YNLGLIIFRD QVVRYGCIRD H LRQTLLDM ...String: MSNLSKGTGS RKDTKMRIRA FPMTMDEKYV NSIWDLLKNA IQEIQRKNNS GLSFEELYRN AYTMVLHKHG EKLYTGLREV VTEHLINKV REDVLNSLNN NFLQTLNQAW NDHQTAMVMI RDILMYMDRV YVQQNNVENV YNLGLIIFRD QVVRYGCIRD H LRQTLLDM IARERKGEVV DRGAIRNACQ MLMILGLEGR SVYEEDFEAP FLEMSAEFFQ MESQKFLAEN SASVYIKKVE AR INEEIER VMHCLDKSTE EPIVKVVERE LISKHMKTIV EMENSGLVHM LKNGKTEDLG CMYKLFSRVP NGLKTMCECM SSY LREQGK ALVSEEGEGK NPVDYIQGLL DLKSRFDRFL LESFNNDRLF KQTIAGDFEY FLNLNSRSPE YLSLFIDDKL KKGV KGLTE QEVETILDKA MVLFRFMQEK DVFERYYKQH LARRLLTNKS VSDDSEKNMI SKLKTECGCQ FTSKLEGMFR DMSIS NTTM DEFRQHLQAT GVSLGGVDLT VRVLTTGYWP TQSATPKCNI PPAPRHAFEI FRRFYLAKHS GRQLTLQHHM GSADLN ATF YGPVKKEDGS EVGVGGAQVT GSNTRKHILQ VSTFQMTILM LFNNREKYTF EEIQQETDIP ERELVRALQS LACGKPT QR VLTKEPKSKE IENGHIFTVN DQFTSKLHRV KIQTVAAKQG ESDPERKETR QKVDDDRKHE IEAAIVRIMK SRKKMQHN V LVAEVTQQLK ARFLPSPVVI KKRIEGLIER EYLARTPEDR KVYTYVA UniProtKB: Cullin-3 |
-Macromolecule #2: E3 ubiquitin-protein ligase RBX1
Macromolecule | Name: E3 ubiquitin-protein ligase RBX1 / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 12.289977 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MAAAMDVDTP SGTNSGAGKK RFEVKKWNAV ALWAWDIVVD NCAICRNHIM DLCIECQANQ ASATSEECTV AWGVCNHAFH FHCISRWLK TRQVCPLDNR EWEFQKYGH UniProtKB: E3 ubiquitin-protein ligase RBX1 |
-Macromolecule #3: Kelch repeat and BTB domain-containing protein 2
Macromolecule | Name: Kelch repeat and BTB domain-containing protein 2 / type: protein_or_peptide / ID: 3 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 71.431375 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MSTQDERQIN TEYAVSLLEQ LKLFYEQQLF TDIVLIVEGT EFPCHKMVLA TCSSYFRAMF MSGLSESKQT HVHLRNVDAA TLQIIITYA YTGNLAMNDS TVEQLYETAC FLQVEDVLQR CREYLIKKIN AENCVRLLSF ADLFSCEELK QSAKRMVEHK F TAVYHQDA ...String: MSTQDERQIN TEYAVSLLEQ LKLFYEQQLF TDIVLIVEGT EFPCHKMVLA TCSSYFRAMF MSGLSESKQT HVHLRNVDAA TLQIIITYA YTGNLAMNDS TVEQLYETAC FLQVEDVLQR CREYLIKKIN AENCVRLLSF ADLFSCEELK QSAKRMVEHK F TAVYHQDA FMQLSHDLLI DILSSDNLNV EKEETVREAA MLWLEYNTES RSQYLSSVLS QIRIDALSEV TQRAWFQGLP PN DKSVVVQ GLYKDMPKFF KPRLGMTKEE MMIFIEASSE NPCSLYSSVC YSPQAEKVYK LCSPPADLHK VGTVVTPDND IYI AGGQVP LKNTKTNHSK TSKLQTAFRT VNCFYWFDAQ QNTWFPKTPM LFVRIKPSLV CCEGYIYAIG GDSVGGELNR RTVE RYDTE KDEWTMVSPL PCAWQWSAAV VVHDCIYVMT LNLMYCYFPR SDSWVEMAMR QTSRSFASAA AFGDKIFYIG GLHIA TNSG IRLPSGTVDG SSVTVEIYDV NKNEWKMAAN IPAKRYSDPC VRAVVISNSL CVFMRETHLN ERAKYVTYQY DLELDR WSL RQHISERVLW DLGRDFRCTV GKLYPSCLEE SPWKPPTYLF STDGTEEFEL DGEMVALPPV UniProtKB: Kelch repeat and BTB domain-containing protein 2 |
-Macromolecule #4: Phosphatidylinositol 3-kinase regulatory subunit alpha
Macromolecule | Name: Phosphatidylinositol 3-kinase regulatory subunit alpha type: protein_or_peptide / ID: 4 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: Homo sapiens (human) |
Molecular weight | Theoretical: 83.710281 KDa |
Recombinant expression | Organism: Spodoptera frugiperda (fall armyworm) |
Sequence | String: MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEARP EEIGWLNGYN ETTGERGDFP GTYVEYIGRK KISPPTPKP RPPRPLPVAP GSSKTEADVE QQALTLPDLA EQFAPPDIAP PLLIKLVEAI EKKGLECSTL YRTQSSSNLA E LRQLLDCD ...String: MSAEGYQYRA LYDYKKEREE DIDLHLGDIL TVNKGSLVAL GFSDGQEARP EEIGWLNGYN ETTGERGDFP GTYVEYIGRK KISPPTPKP RPPRPLPVAP GSSKTEADVE QQALTLPDLA EQFAPPDIAP PLLIKLVEAI EKKGLECSTL YRTQSSSNLA E LRQLLDCD TPSVDLEMID VHVLADAFKR YLLDLPNPVI PAAVYSEMIS LAPEVQSSEE YIQLLKKLIR SPSIPHQYWL TL QYLLKHF FKLSQTSSKN LLNARVLSEI FSPMLFRFSA ASSDNTENLI KVIEILISTE WNERQPAPAL PPKPPKPTTV ANN GMNNNM SLQDAEWYWG DISREEVNEK LRDTADGTFL VRDASTKMHG DYTLTLRKGG NNKLIKIFHR DGKYGFSDPL TFSS VVELI NHYRNESLAQ YNPKLDVKLL YPVSKYQQDQ VVKEDNIEAV GKKLHEYNTQ FQEKSREYDR LYEEYTRTSQ EIQMK RTAI EAFNETIKIF EEQCQTQERY SKEYIEKFKR EGNEKEIQRI MHNYDKLKSR ISEIIDSRRR LEEDLKKQAA EYREID KRM NSIKPDLIQL RKTRDQYLMW LTQKGVRQKK LNEWLGNENT EDQYSLVEDD EDLPHHDEKT WNVGSSNRNK AENLLRG KR DGTFLVRESS KQGCYACSVV VDGEVKHCVI NKTATGYGFA EPYNLYSSLK ELVLHYQHTS LVQHNDSLNV TLAYPVYA Q QRR UniProtKB: Phosphatidylinositol 3-kinase regulatory subunit alpha |
-Macromolecule #5: ZINC ION
Macromolecule | Name: ZINC ION / type: ligand / ID: 5 / Number of copies: 12 / Formula: ZN |
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Molecular weight | Theoretical: 65.409 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 8.5 |
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Vitrification | Cryogen name: ETHANE |
-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: 45.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
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 |
-Image processing
Startup model | Type of model: PDB ENTRY PDB model - PDB ID: Details: 7CIO |
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Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 7.52 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 239068 |
Initial angle assignment | Type: PROJECTION MATCHING |
Final angle assignment | Type: PROJECTION MATCHING |