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Yorodumi- EMDB-16936: cGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure) -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-16936 | |||||||||
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Title | cGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure) | |||||||||
Map data | ||||||||||
Sample |
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Keywords | cGAS / degradation / UPS / IMMUNE SYSTEM | |||||||||
Function / homology | Function and homology information cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / target-directed miRNA degradation / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / elongin complex / VCB complex / regulation of immunoglobulin production / cGAS/STING signaling pathway ...cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / STING mediated induction of host immune responses / target-directed miRNA degradation / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / elongin complex / VCB complex / regulation of immunoglobulin production / cGAS/STING signaling pathway / Cul5-RING ubiquitin ligase complex / pattern recognition receptor signaling pathway / regulation of T cell activation / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / STAT family protein binding / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / ubiquitin-like protein ligase binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / positive regulation of type I interferon production / Tat-mediated elongation of the HIV-1 transcript / negative regulation of megakaryocyte differentiation / Formation of HIV-1 elongation complex containing HIV-1 Tat / protein localization to CENP-A containing chromatin / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of double-strand break repair via homologous recombination / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / RNA Polymerase II Transcription Elongation / Packaging Of Telomere Ends / Formation of RNA Pol II elongation complex / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / nucleosome binding / Deposition of new CENPA-containing nucleosomes at the centromere / positive regulation of defense response to virus by host / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / RNA Polymerase II Pre-transcription Events / Inhibition of DNA recombination at telomere / Meiotic synapsis / phosphatidylinositol-4,5-bisphosphate binding / telomere organization / activation of innate immune response / RNA Polymerase I Promoter Opening / Interleukin-7 signaling / Assembly of the ORC complex at the origin of replication / SUMOylation of chromatin organization proteins / cAMP-mediated signaling / DNA methylation / transcription corepressor binding / Condensation of Prophase Chromosomes / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / molecular condensate scaffold activity / PRC2 methylates histones and DNA / Defective pyroptosis / HDACs deacetylate histones / transcription elongation by RNA polymerase II / determination of adult lifespan / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / RNA Polymerase I Promoter Escape / Nonhomologous End-Joining (NHEJ) / Transcriptional regulation by small RNAs / Vif-mediated degradation of APOBEC3G / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / G2/M DNA damage checkpoint / Inactivation of CSF3 (G-CSF) signaling / HDMs demethylate histones / B-WICH complex positively regulates rRNA expression / DNA Damage/Telomere Stress Induced Senescence / Evasion by RSV of host interferon responses / Metalloprotease DUBs / PKMTs methylate histone lysines / Meiotic recombination / RMTs methylate histone arginines / Pre-NOTCH Transcription and Translation / Regulation of expression of SLITs and ROBOs / Activation of anterior HOX genes in hindbrain development during early embryogenesis / HCMV Early Events / Transcriptional regulation of granulopoiesis / structural constituent of chromatin / positive regulation of cellular senescence / UCH proteinases / nucleosome / nucleosome assembly Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.5 Å | |||||||||
Authors | Xu PB / Ablasser A | |||||||||
Funding support | European Union, 1 items
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Citation | Journal: Nature / Year: 2024 Title: The CRL5-SPSB3 ubiquitin ligase targets nuclear cGAS for degradation. Authors: Pengbiao Xu / Ying Liu / Chong Liu / Baptiste Guey / Lingyun Li / Pauline Melenec / Jonathan Ricci / Andrea Ablasser / Abstract: Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP). ...Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2'3'-cyclic GMP-AMP (cGAMP). The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin-RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_16936.map.gz | 43 MB | EMDB map data format | |
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Header (meta data) | emd-16936-v30.xml emd-16936.xml | 22.2 KB 22.2 KB | Display Display | EMDB header |
Images | emd_16936.png | 61.3 KB | ||
Filedesc metadata | emd-16936.cif.gz | 7.2 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-16936 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-16936 | HTTPS FTP |
-Validation report
Summary document | emd_16936_validation.pdf.gz | 434 KB | Display | EMDB validaton report |
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Full document | emd_16936_full_validation.pdf.gz | 433.6 KB | Display | |
Data in XML | emd_16936_validation.xml.gz | 6.7 KB | Display | |
Data in CIF | emd_16936_validation.cif.gz | 7.6 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16936 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-16936 | HTTPS FTP |
-Related structure data
Related structure data | 8ol1MC 8okxC C: citing same article (ref.) M: atomic model generated by this map |
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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_16936.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Voxel size | X=Y=Z: 1.268 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Sample components
+Entire : cGAS-Spsb3-EloBC complex
+Supramolecule #1: cGAS-Spsb3-EloBC complex
+Macromolecule #1: Histone H3.2
+Macromolecule #2: Histone H4
+Macromolecule #3: Histone H2A type 1-H
+Macromolecule #4: Histone H2B type 1-H
+Macromolecule #5: Histone H2A type 1-J
+Macromolecule #6: Histone H2B type 1-N
+Macromolecule #9: Cyclic GMP-AMP synthase
+Macromolecule #10: SPRY domain-containing SOCS box protein 3
+Macromolecule #11: Elongin-C
+Macromolecule #12: Elongin-B
+Macromolecule #7: DNA (145-MER)
+Macromolecule #8: DNA (145-MER)
+Macromolecule #13: ZINC ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.4 / Details: PBS buffer |
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Vitrification | Cryogen name: ETHANE |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 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: 2.0 µm / Nominal defocus min: 0.6 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: INSILICO MODEL In silico model: alphafold2 prediction of individual proteins |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 592494 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |