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Yorodumi- EMDB-22206: Two mouse cGAS catalytic domain binding to human assembled nucleosome -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-22206 | |||||||||
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Title | Two mouse cGAS catalytic domain binding to human assembled nucleosome | |||||||||
Map data | two mouse cGAS binds to reconstituted human nucleosome | |||||||||
Sample |
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Keywords | Immunity / IMMUNE SYSTEM / IMMUNE SYSTEM-DNA complex | |||||||||
Function / homology | Function and homology information regulation of type I interferon production / cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / negative regulation of DNA repair / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / negative regulation of cGAS/STING signaling pathway ...regulation of type I interferon production / cyclic GMP-AMP synthase / 2',3'-cyclic GMP-AMP synthase activity / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / negative regulation of DNA repair / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / regulation of immune response / positive regulation of type I interferon production / Replacement of protamines by nucleosomes in the male pronucleus / arachidonate 15-lipoxygenase / arachidonate 15-lipoxygenase activity / nucleosome binding / Packaging Of Telomere Ends / 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 / Deposition of new CENPA-containing nucleosomes at the centromere / 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 / nucleosomal DNA binding / 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 / PRC2 methylates histones and DNA / molecular condensate scaffold activity / Defective pyroptosis / Meiotic recombination / innate immune response in mucosa / 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 / Transcriptional regulation of granulopoiesis / HDMs demethylate histones / Formation of the beta-catenin:TCF transactivating complex / HCMV Early Events / 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 / heterochromatin formation / RMTs methylate histone arginines / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / Activation of anterior HOX genes in hindbrain development during early embryogenesis / structural constituent of chromatin / positive regulation of cellular senescence / UCH proteinases / nucleosome / antimicrobial humoral immune response mediated by antimicrobial peptide / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / nucleosome assembly / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / chromatin organization / E3 ubiquitin ligases ubiquitinate target proteins / double-stranded DNA binding / Senescence-Associated Secretory Phenotype (SASP) / RUNX1 regulates transcription of genes involved in differentiation of HSCs / HATs acetylate histones / site of double-strand break / antibacterial humoral response / Oxidative Stress Induced Senescence / defense response to virus / Estrogen-dependent gene expression / nuclear body / Ub-specific processing proteases / defense response to Gram-positive bacterium / protein heterodimerization activity / Amyloid fiber formation / DNA repair / innate immune response Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) / Mus musculus (house mouse) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 6.8 Å | |||||||||
Authors | Xu P / Li P | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Nature / Year: 2020 Title: The molecular basis of tight nuclear tethering and inactivation of cGAS. Authors: Baoyu Zhao / Pengbiao Xu / Chesley M Rowlett / Tao Jing / Omkar Shinde / Yuanjiu Lei / A Phillip West / Wenshe Ray Liu / Pingwei Li / Abstract: Nucleic acids derived from pathogens induce potent innate immune responses. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor that catalyses the synthesis of the cyclic dinucleotide ...Nucleic acids derived from pathogens induce potent innate immune responses. Cyclic GMP-AMP synthase (cGAS) is a double-stranded DNA sensor that catalyses the synthesis of the cyclic dinucleotide cyclic GMP-AMP, which mediates the induction of type I interferons through the STING-TBK1-IRF3 signalling axis. cGAS was previously thought to not react with self DNA owing to its cytosolic localization; however, recent studies have shown that cGAS is localized mostly in the nucleus and has low activity as a result of tight nuclear tethering. Here we show that cGAS binds to nucleosomes with nanomolar affinity and that nucleosome binding potently inhibits its catalytic activity. To elucidate the molecular basis of cGAS inactivation by nuclear tethering, we determined the structure of mouse cGAS bound to human nucleosome by cryo-electron microscopy. The structure shows that cGAS binds to a negatively charged acidic patch formed by histones H2A and H2B via its second DNA-binding site. High-affinity nucleosome binding blocks double-stranded DNA binding and maintains cGAS in an inactive conformation. Mutations of cGAS that disrupt nucleosome binding alter cGAS-mediated signalling in cells. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_22206.map.gz | 4 MB | EMDB map data format | |
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Header (meta data) | emd-22206-v30.xml emd-22206.xml | 20.7 KB 20.7 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_22206_fsc.xml | 7.8 KB | Display | FSC data file |
Images | emd_22206.png | 86.3 KB | ||
Filedesc metadata | emd-22206.cif.gz | 6.6 KB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-22206 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-22206 | HTTPS FTP |
-Validation report
Summary document | emd_22206_validation.pdf.gz | 396.4 KB | Display | EMDB validaton report |
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Full document | emd_22206_full_validation.pdf.gz | 396 KB | Display | |
Data in XML | emd_22206_validation.xml.gz | 10.1 KB | Display | |
Data in CIF | emd_22206_validation.cif.gz | 13 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22206 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-22206 | HTTPS FTP |
-Related structure data
Related structure data | 6xjdMC 6x59C 6x5aC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_22206.map.gz / Format: CCP4 / Size: 38.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | two mouse cGAS binds to reconstituted human nucleosome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Sample components
+Entire : cGAS-nucleosome complex
+Supramolecule #1: cGAS-nucleosome complex
+Supramolecule #2: Histone
+Supramolecule #3: DNA
+Supramolecule #4: Cyclic GMP-AMP synthase
+Macromolecule #1: Histone H3.2
+Macromolecule #2: Histone H4
+Macromolecule #3: Histone H2A type 1
+Macromolecule #4: Histone H2B type 1-C/E/F/G/I
+Macromolecule #7: Cyclic GMP-AMP synthase
+Macromolecule #5: DNA (145-MER)
+Macromolecule #6: DNA (145-MER)
+Macromolecule #8: ZINC ION
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Concentration | 0.4 mg/mL |
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Buffer | pH: 7.4 |
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 48.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.7000000000000001 µm |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |