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Yorodumi- PDB-8ol1: cGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure) -
+Open data
-Basic information
Entry | Database: PDB / ID: 8ol1 | ||||||
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Title | cGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure) | ||||||
Components |
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Keywords | IMMUNE SYSTEM / cGAS / degradation / UPS | ||||||
Function / homology | Function and homology information STAT family protein binding / 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 ...STAT family protein binding / 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 / 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 / Replacement of protamines by nucleosomes in the male pronucleus / Tat-mediated elongation of the HIV-1 transcript / arachidonate 15-lipoxygenase / arachidonate 15-lipoxygenase activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / nucleosome binding / Packaging Of Telomere Ends / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of double-strand break repair via homologous recombination / lipoxygenase pathway / Recognition and association of DNA glycosylase with site containing an affected purine / Cleavage of the damaged purine / arachidonate metabolic process / Chromatin modifying enzymes / lipid oxidation / RNA Polymerase II Transcription Elongation / Deposition of new CENPA-containing nucleosomes at the centromere / Formation of RNA Pol II elongation complex / hepoxilin biosynthetic process / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / linoleic acid metabolic process / Meiotic synapsis / Inhibition of DNA recombination at telomere / positive regulation of defense response to virus by host / RNA Polymerase II Pre-transcription Events / RNA Polymerase I Promoter Opening / phosphatidylinositol-4,5-bisphosphate binding / Assembly of the ORC complex at the origin of replication / activation of innate immune response / Interleukin-7 signaling / DNA methylation / cAMP-mediated signaling / Condensation of Prophase Chromosomes / HCMV Late Events / SIRT1 negatively regulates rRNA expression / Chromatin modifications during the maternal to zygotic transition (MZT) / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / transcription corepressor binding / PRC2 methylates histones and DNA / molecular condensate scaffold activity / Defective pyroptosis / Meiotic recombination / DNA Damage/Telomere Stress Induced Senescence / HDACs deacetylate histones / Nonhomologous End-Joining (NHEJ) / RNA Polymerase I Promoter Escape / determination of adult lifespan / Transcriptional regulation by small RNAs / transcription initiation at RNA polymerase II promoter / TP53 Regulates Transcription of DNA Repair Genes / Transcriptional regulation of granulopoiesis / transcription elongation by RNA polymerase II / HDMs demethylate histones / Formation of the beta-catenin:TCF transactivating complex / HCMV Early Events / Vif-mediated degradation of APOBEC3G / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / G2/M DNA damage checkpoint / NoRC negatively regulates rRNA expression / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / PKMTs methylate histone lysines / B-WICH complex positively regulates rRNA expression / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / RMTs methylate histone arginines / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Regulation of expression of SLITs and ROBOs / structural constituent of chromatin / positive regulation of cellular senescence / UCH proteinases Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å | ||||||
Authors | Xu, P.B. / Ablasser, A. | ||||||
Funding support | European Union, 1items
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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
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8ol1.cif.gz | 433.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8ol1.ent.gz | 326.6 KB | Display | PDB format |
PDBx/mmJSON format | 8ol1.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8ol1_validation.pdf.gz | 847.6 KB | Display | wwPDB validaton report |
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Full document | 8ol1_full_validation.pdf.gz | 927.5 KB | Display | |
Data in XML | 8ol1_validation.xml.gz | 52.2 KB | Display | |
Data in CIF | 8ol1_validation.cif.gz | 83.9 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ol/8ol1 ftp://data.pdbj.org/pub/pdb/validation_reports/ol/8ol1 | HTTPS FTP |
-Related structure data
Related structure data | 16936MC 8okxC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 6 types, 8 molecules AEBFKLMN
#1: Protein | Mass: 11546.513 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: H3C15, HIST2H3A, H3C14, H3F2, H3FM, HIST2H3C, H3C13, HIST2H3D Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q71DI3 #2: Protein | Mass: 9180.745 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) Gene: H4C1, H4/A, H4FA, HIST1H4A, H4C2, H4/I, H4FI, HIST1H4B, H4C3, H4/G, H4FG, HIST1H4C, H4C4, H4/B, H4FB, HIST1H4D, H4C5, H4/J, H4FJ, HIST1H4E, H4C6, H4/C, H4FC, HIST1H4F, H4C8, H4/H, H4FH, ...Gene: H4C1, H4/A, H4FA, HIST1H4A, H4C2, H4/I, H4FI, HIST1H4B, H4C3, H4/G, H4FG, HIST1H4C, H4C4, H4/B, H4FB, HIST1H4D, H4C5, H4/J, H4FJ, HIST1H4E, H4C6, H4/C, H4FC, HIST1H4F, H4C8, H4/H, H4FH, HIST1H4H, H4C9, H4/M, H4FM, HIST1H4I, H4C11, H4/E, H4FE, HIST1H4J, H4C12, H4/D, H4FD, HIST1H4K, H4C13, H4/K, H4FK, HIST1H4L, H4C14, H4/N, H4F2, H4FN, HIST2H4, HIST2H4A, H4C15, H4/O, H4FO, HIST2H4B, H4C16, H4-16, HIST4H4 Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62805 #9: Protein | | Mass: 42202.590 Da / Num. of mol.: 1 / Mutation: K285A R300A K428A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CGAS, C6orf150, MB21D1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q8N884, cyclic GMP-AMP synthase #10: Protein | | Mass: 27415.240 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: SPSB3, C16orf31, SSB3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q6PJ21 #11: Protein | | Mass: 12485.135 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369 #12: Protein | | Mass: 13147.781 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15370 |
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-Histone H2A type 1- ... , 2 types, 2 molecules CG
#3: Protein | Mass: 11763.755 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2AC12, HIST1H2AH, HIST1H2AI / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q96KK5 |
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#5: Protein | Mass: 11666.640 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2AC14, H2AFE, HIST1H2AJ / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q99878 |
-Histone H2B type 1- ... , 2 types, 2 molecules DH
#4: Protein | Mass: 10623.174 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC9, H2BFJ, HIST1H2BH / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q93079 |
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#6: Protein | Mass: 10493.994 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: H2BC15, H2BFD, HIST1H2BN / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q99877 |
-DNA chain , 2 types, 2 molecules IJ
#7: DNA chain | Mass: 44552.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) |
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#8: DNA chain | Mass: 44961.633 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) |
-Non-polymers , 1 types, 1 molecules
#13: Chemical | ChemComp-ZN / |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: cGAS-Spsb3-EloBC complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Escherichia coli BL21(DE3) (bacteria) |
Buffer solution | pH: 7.4 / Details: PBS buffer |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20rc2_4400: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 592494 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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