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- EMDB-22409: 2:1 cGAS-nucleosome complex -

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Basic information

Entry
Database: EMDB / ID: EMD-22409
Title2:1 cGAS-nucleosome complex
Map data
Sample2:1 cGAS-nucleosome complex:
Histone H3.2 / Histone H4 / Histone H2A type 1 / Histone H2B type 1-C/E/F/G/I / (nucleic-acidNucleic acid) x 2 / Cyclic GMP-AMP synthase / ligand
Function / homology
Function and homology information


cyclic GMP-AMP synthase / positive regulation of cGMP-mediated signaling / 2',3'-cyclic GMP-AMP synthase activity / regulation of type I interferon production / paracrine signaling / regulation of immunoglobulin production / negative regulation of double-strand break repair via homologous recombination / regulation of T cell activation / cellular response to exogenous dsRNA / positive regulation of cAMP-mediated signaling ...cyclic GMP-AMP synthase / positive regulation of cGMP-mediated signaling / 2',3'-cyclic GMP-AMP synthase activity / regulation of type I interferon production / paracrine signaling / regulation of immunoglobulin production / negative regulation of double-strand break repair via homologous recombination / regulation of T cell activation / cellular response to exogenous dsRNA / positive regulation of cAMP-mediated signaling / positive regulation of type I interferon production / negative regulation of megakaryocyte differentiation / Packaging Of Telomere Ends / Chromatin modifying enzymes / Cleavage of the damaged purine / Recognition and association of DNA glycosylase with site containing an affected purine / Deposition of new CENPA-containing nucleosomes at the centromere / regulation of immune response / DNA replication-independent chromatin assembly / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / Inhibition of DNA recombination at telomere / Meiotic synapsis / heterochromatin assembly => GO:0031507 / telomere organization / RNA Polymerase I Promoter Opening / SUMOylation of chromatin organization proteins / Interleukin-7 signaling / determination of adult lifespan / DNA replication-dependent chromatin assembly / DNA methylation / positive regulation of defense response to virus by host / innate immune response in mucosa / HCMV Late Events / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / Condensation of Prophase Chromosomes / PRC2 methylates histones and DNA / activation of innate immune response / Defective pyroptosis / RNA Polymerase I Promoter Escape / HDACs deacetylate histones / nuclear chromosome / Transcriptional regulation by small RNAs / NoRC negatively regulates rRNA expression / Nonhomologous End-Joining (NHEJ) / phosphatidylinositol-4,5-bisphosphate binding / Formation of the beta-catenin:TCF transactivating complex / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / B-WICH complex positively regulates rRNA expression / DNA-templated transcription, initiation / Metalloprotease DUBs / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / DNA Damage/Telomere Stress Induced Senescence / G2/M DNA damage checkpoint / RMTs methylate histone arginines / nucleosome assembly / HCMV Early Events / HDMs demethylate histones / Pre-NOTCH Transcription and Translation / Meiotic recombination / PKMTs methylate histone lysines / nucleosome / Activation of anterior HOX genes in hindbrain development during early embryogenesis / UCH proteinases / Transcriptional regulation of granulopoiesis / site of double-strand break / positive regulation of cellular senescence / E3 ubiquitin ligases ubiquitinate target proteins / RUNX1 regulates transcription of genes involved in differentiation of HSCs / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / Processing of DNA double-strand break ends / Factors involved in megakaryocyte development and platelet production / HATs acetylate histones / double-stranded DNA binding / Senescence-Associated Secretory Phenotype (SASP) / defense response to virus / chromosome, telomeric region / Oxidative Stress Induced Senescence / antibacterial humoral response / Estrogen-dependent gene expression / antimicrobial humoral immune response mediated by antimicrobial peptide / Ub-specific processing proteases / defense response to Gram-positive bacterium / protein heterodimerization activity / Amyloid fiber formation / DNA repair / protein domain specific binding / cellular response to DNA damage stimulus / GTP binding / chromatin binding / innate immune response / enzyme binding / protein-containing complex / RNA binding / DNA binding / extracellular space / extracellular exosome / membrane / extracellular region
Similarity search - Function
Mab-21 / Mab-21 domain / Mab-21 protein nucleotidyltransferase domain / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A signature. / Histone H2A conserved site / Histone H2A, C-terminal domain / C-terminus of histone H2A ...Mab-21 / Mab-21 domain / Mab-21 protein nucleotidyltransferase domain / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A signature. / Histone H2A conserved site / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone 2A / Histone H2A / Histone H4 signature. / Histone H4, conserved site / Histone H4 / Histone H4 / Centromere kinetochore component CENP-T histone fold / CENP-T/Histone H4, histone fold / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF) / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Core histone H2A/H2B/H3/H4 / Histone H2A/H2B/H3 / Histone-fold
Similarity search - Domain/homology
Histone H2A type 1 / Histone H4 / Histone H2B type 1-C/E/F/G/I / Histone H3.2 / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsBoyer JA / Spangler CJ / Strauss JD / Cesmat AP / Liu P / McGinty RK / Zhang Q
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM133498 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R21CA234979 United States
CitationJournal: Science / Year: 2020
Title: Structural basis of nucleosome-dependent cGAS inhibition.
Authors: Joshua A Boyer / Cathy J Spangler / Joshua D Strauss / Andrew P Cesmat / Pengda Liu / Robert K McGinty / Qi Zhang /
Abstract: Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory ...Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) recognizes cytosolic foreign or damaged DNA to activate the innate immune response to infection, inflammatory diseases, and cancer. By contrast, cGAS reactivity against self-DNA in the nucleus is suppressed by chromatin tethering. We report a 3.3-angstrom-resolution cryo-electron microscopy structure of cGAS in complex with the nucleosome core particle. The structure reveals that cGAS uses two conserved arginines to anchor to the nucleosome acidic patch. The nucleosome-binding interface exclusively occupies the strong double-stranded DNA (dsDNA)-binding surface on cGAS and sterically prevents cGAS from oligomerizing into the functionally active 2:2 cGAS-dsDNA state. These findings provide a structural basis for how cGAS maintains an inhibited state in the nucleus and further exemplify the role of the nucleosome in regulating diverse nuclear protein functions.
History
DepositionAug 6, 2020-
Header (metadata) releaseSep 16, 2020-
Map releaseSep 16, 2020-
UpdateNov 4, 2020-
Current statusNov 4, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7joa
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22409.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.91 Å/pix.
x 330 pix.
= 300.3 Å
0.91 Å/pix.
x 330 pix.
= 300.3 Å
0.91 Å/pix.
x 330 pix.
= 300.3 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.91 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.050699998 - 0.11056035
Average (Standard dev.)0.00017941065 (±0.0025300693)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 300.30002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.910.910.91
M x/y/z330330330
origin x/y/z0.0000.0000.000
length x/y/z300.300300.300300.300
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS330330330
D min/max/mean-0.0510.1110.000

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Supplemental data

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Sample components

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Entire 2:1 cGAS-nucleosome complex

EntireName: 2:1 cGAS-nucleosome complex / Details: cGAS bound to the nucleosome in a 2:1 ratio / Number of Components: 9

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Component #1: protein, 2:1 cGAS-nucleosome complex

ProteinName: 2:1 cGAS-nucleosome complex / Details: cGAS bound to the nucleosome in a 2:1 ratio / Recombinant expression: No
MassTheoretical: 290 kDa
SourceSpecies: Homo sapiens (human)

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Component #2: protein, Histone H3.2

ProteinName: Histone H3.2 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 15.421101 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #3: protein, Histone H4

ProteinName: Histone H4 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 11.394426 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #4: protein, Histone H2A type 1

ProteinName: Histone H2A type 1 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 13.990342 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #5: protein, Histone H2B type 1-C/E/F/G/I

ProteinName: Histone H2B type 1-C/E/F/G/I / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 13.806018 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #6: nucleic-acid, DNA (145-MER)

nucleic acidName: DNA (145-MER) / Class: DNA / Structure: OTHER / Synthetic: No
Sequence: (DA)(DT)(DC)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC)(DC)(DT)(DG)(DG) (DA)(DG)(DA)(DC)(DT)(DA)(DG)(DG)(DG)(DA) (DG)(DT)(DA)(DA)(DT)(DC) ...Sequence:
(DA)(DT)(DC)(DG)(DG)(DA)(DT)(DG)(DT)(DA) (DT)(DA)(DT)(DA)(DT)(DC)(DT)(DG)(DA)(DC) (DA)(DC)(DG)(DT)(DG)(DC)(DC)(DT)(DG)(DG) (DA)(DG)(DA)(DC)(DT)(DA)(DG)(DG)(DG)(DA) (DG)(DT)(DA)(DA)(DT)(DC)(DC)(DC)(DC)(DT) (DT)(DG)(DG)(DC)(DG)(DG)(DT)(DT)(DA)(DA) (DA)(DA)(DC)(DG)(DC)(DG)(DG)(DG)(DG)(DG) (DA)(DC)(DA)(DG)(DC)(DG)(DC)(DG)(DT)(DA) (DC)(DG)(DT)(DG)(DC)(DG)(DT)(DT)(DT)(DA) (DA)(DG)(DC)(DG)(DG)(DT)(DG)(DC)(DT)(DA) (DG)(DA)(DG)(DC)(DT)(DG)(DT)(DC)(DT)(DA) (DC)(DG)(DA)(DC)(DC)(DA)(DA)(DT)(DT)(DG) (DA)(DG)(DC)(DG)(DG)(DC)(DC)(DT)(DC)(DG) (DG)(DC)(DA)(DC)(DC)(DG)(DG)(DG)(DA)(DT) (DT)(DC)(DT)(DC)(DG)(DA)(DT)
MassTheoretical: 45.610043 kDa
SourceSpecies: synthetic construct (others)

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Component #7: nucleic-acid, DNA (145-MER)

nucleic acidName: DNA (145-MER) / Class: DNA / Structure: OTHER / Synthetic: No
Sequence: (DA)(DT)(DC)(DG)(DA)(DG)(DA)(DA)(DT)(DC) (DC)(DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA) (DG)(DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA)(DC)(DA)(DG)(DC)(DT) ...Sequence:
(DA)(DT)(DC)(DG)(DA)(DG)(DA)(DA)(DT)(DC) (DC)(DC)(DG)(DG)(DT)(DG)(DC)(DC)(DG)(DA) (DG)(DG)(DC)(DC)(DG)(DC)(DT)(DC)(DA)(DA) (DT)(DT)(DG)(DG)(DT)(DC)(DG)(DT)(DA)(DG) (DA)(DC)(DA)(DG)(DC)(DT)(DC)(DT)(DA)(DG) (DC)(DA)(DC)(DC)(DG)(DC)(DT)(DT)(DA)(DA) (DA)(DC)(DG)(DC)(DA)(DC)(DG)(DT)(DA)(DC) (DG)(DC)(DG)(DC)(DT)(DG)(DT)(DC)(DC)(DC) (DC)(DC)(DG)(DC)(DG)(DT)(DT)(DT)(DT)(DA) (DA)(DC)(DC)(DG)(DC)(DC)(DA)(DA)(DG)(DG) (DG)(DG)(DA)(DT)(DT)(DA)(DC)(DT)(DC)(DC) (DC)(DT)(DA)(DG)(DT)(DC)(DT)(DC)(DC)(DA) (DG)(DG)(DC)(DA)(DC)(DG)(DT)(DG)(DT)(DC) (DA)(DG)(DA)(DT)(DA)(DT)(DA)(DT)(DA)(DC) (DA)(DT)(DC)(DC)(DG)(DA)(DT)
MassTheoretical: 45.13877 kDa
SourceSpecies: synthetic construct (others)

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Component #8: protein, Cyclic GMP-AMP synthase

ProteinName: Cyclic GMP-AMP synthase / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 42.984664 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #9: ligand, ZINC ION

LigandName: ZINC ION / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 6.540905 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 1 mg/mL / pH: 7.5
Support filmInstrument: Pelco easiGlow
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen Name: ETHANE / Temperature: 293 K / Humidity: 95 %

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
ImagingMicroscope: FEI TALOS ARCTICA
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 200 kV / Electron Dose: 53 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image acquisition

Image acquisitionNumber of Digital Images: 2100

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Image processing

ProcessingMethod: single particle reconstruction / Applied Symmetry: C2 (2 fold cyclic) / Number of Projections: 45587
3D reconstructionSoftware: RELION / Resolution: 3.3 Å / Resolution Method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement space: REAL
Input PDB model: 6FQ5, 4K8V
Output model

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