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- PDB-8ol1: cGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure) -

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Basic information

Entry
Database: PDB / ID: 8ol1
TitlecGAS-Nucleosome in complex with SPSB3-ELOBC (composite structure)
Components
  • (DNA (145-MER)) x 2
  • (Histone H2A type 1- ...) x 2
  • (Histone H2B type 1- ...) x 2
  • Cyclic GMP-AMP synthase
  • Elongin-B
  • Elongin-C
  • Histone H3.2
  • Histone H4
  • SPRY domain-containing SOCS box protein 3
KeywordsIMMUNE SYSTEM / cGAS / degradation / UPS
Function / homology
Function and homology information


2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / target-directed miRNA degradation / VCB complex / elongin complex / regulation of immunoglobulin production / cGAS/STING signaling pathway ...2',3'-cyclic GMP-AMP synthase activity / cyclic GMP-AMP synthase / STING mediated induction of host immune responses / paracrine signaling / poly-ADP-D-ribose modification-dependent protein binding / target-directed miRNA degradation / VCB complex / elongin complex / regulation of immunoglobulin production / cGAS/STING signaling pathway / regulation of T cell activation / Cul5-RING ubiquitin ligase complex / pattern recognition receptor signaling pathway / cGMP-mediated signaling / SCF ubiquitin ligase complex / negative regulation of epithelial to mesenchymal transition / Cul2-RING ubiquitin ligase complex / STAT family protein binding / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cellular response to exogenous dsRNA / RSV-host interactions / 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 / ubiquitin-like ligase-substrate adaptor activity / negative regulation of double-strand break repair via homologous recombination / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of megakaryocyte differentiation / protein localization to CENP-A containing chromatin / Formation of HIV elongation complex in the absence of HIV Tat / protein K48-linked ubiquitination / cAMP-mediated signaling / Chromatin modifying enzymes / Replacement of protamines by nucleosomes in the male pronucleus / CENP-A containing nucleosome / nucleosome binding / 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 / positive regulation of defense response to virus by host / phosphatidylinositol-4,5-bisphosphate binding / Recognition and association of DNA glycosylase with site containing an affected pyrimidine / Cleavage of the damaged pyrimidine / RNA Polymerase II Pre-transcription Events / Deposition of new CENPA-containing nucleosomes at the centromere / telomere organization / Inhibition of DNA recombination at telomere / Meiotic synapsis / Interleukin-7 signaling / RNA Polymerase I Promoter Opening / activation of innate immune response / Assembly of the ORC complex at the origin of replication / Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex / SUMOylation of chromatin organization proteins / DNA methylation / Condensation of Prophase Chromosomes / Chromatin modifications during the maternal to zygotic transition (MZT) / HCMV Late Events / SIRT1 negatively regulates rRNA expression / ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression / PRC2 methylates histones and DNA / transcription corepressor binding / Regulation of endogenous retroelements by KRAB-ZFP proteins / Defective pyroptosis / determination of adult lifespan / Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs) / HDACs deacetylate histones / Nonhomologous End-Joining (NHEJ) / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / RNA Polymerase I Promoter Escape / transcription elongation by RNA polymerase II / Transcriptional regulation by small RNAs / Formation of the beta-catenin:TCF transactivating complex / molecular condensate scaffold activity / Vif-mediated degradation of APOBEC3G / RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function / Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3 / G2/M DNA damage checkpoint / HDMs demethylate histones / Inactivation of CSF3 (G-CSF) signaling / NoRC negatively regulates rRNA expression / Evasion by RSV of host interferon responses / DNA Damage/Telomere Stress Induced Senescence / B-WICH complex positively regulates rRNA expression / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / PKMTs methylate histone lysines / Meiotic recombination / Pre-NOTCH Transcription and Translation / Metalloprotease DUBs / RMTs methylate histone arginines / Activation of anterior HOX genes in hindbrain development during early embryogenesis / Regulation of expression of SLITs and ROBOs
Similarity search - Function
SPRY domain-containing SOCS box protein 3, SPRY domain / : / SOCS box domain / SOCS box domain profile. / SOCS_box / Mab-21-like, nucleotidyltransferase domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain ...SPRY domain-containing SOCS box protein 3, SPRY domain / : / SOCS box domain / SOCS box domain profile. / SOCS_box / Mab-21-like, nucleotidyltransferase domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 / Elongin-C / Elongin B / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SPRY domain / B30.2/SPRY domain / B30.2/SPRY domain profile. / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SPRY domain / SKP1/BTB/POZ domain superfamily / : / Histone H2B signature. / Histone H2B / Histone H2B / Histone H2A conserved site / Histone H2A signature. / Histone H2A, C-terminal domain / C-terminus of histone H2A / Histone H2A / Histone 2A / TATA box binding protein associated factor / TATA box binding protein associated factor (TAF), histone-like fold domain / Histone H4, conserved site / Histone H4 signature. / Histone H4 / Histone H4 / CENP-T/Histone H4, histone fold / Centromere kinetochore component CENP-T histone fold / Histone H3 signature 1. / Histone H3 signature 2. / Histone H3 / Histone H3/CENP-A / Histone H2A/H2B/H3 / Core histone H2A/H2B/H3/H4 / Histone-fold / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Concanavalin A-like lectin/glucanase domain superfamily / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
DNA / DNA (> 10) / DNA (> 100) / Histone H4 / Elongin-C / Elongin-B / SPRY domain-containing SOCS box protein 3 / Histone H3.2 / Cyclic GMP-AMP synthase / Histone H2B type 1-H ...DNA / DNA (> 10) / DNA (> 100) / Histone H4 / Elongin-C / Elongin-B / SPRY domain-containing SOCS box protein 3 / Histone H3.2 / Cyclic GMP-AMP synthase / Histone H2B type 1-H / Histone H2A type 1-H / Histone H2B type 1-N / Histone H2A type 1-J
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsXu, P.B. / Ablasser, A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Molecular Biology Organization (EMBO)ALTF 184-2021European Union
CitationJournal: 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
DepositionMar 29, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 14, 2024Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2024Group: Database references / Category: citation / citation_author / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 10, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Histone H3.2
B: Histone H4
C: Histone H2A type 1-H
D: Histone H2B type 1-H
E: Histone H3.2
F: Histone H4
G: Histone H2A type 1-J
H: Histone H2B type 1-N
I: DNA (145-MER)
J: DNA (145-MER)
K: Cyclic GMP-AMP synthase
L: SPRY domain-containing SOCS box protein 3
M: Elongin-C
N: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)270,83215
Polymers270,76714
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 6 types, 8 molecules AEBFKLMN

#1: Protein Histone H3.2 / H3-clustered histone 13 / H3-clustered histone 14 / H3-clustered histone 15 / Histone H3/m / Histone H3/o


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 Histone H4


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 Cyclic GMP-AMP synthase / cGAMP synthase / cGAS / h-cGAS / 2'3'-cGAMP synthase / Mab-21 domain-containing protein 1


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 SPRY domain-containing SOCS box protein 3 / SSB-3


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 Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


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 Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


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 Histone H2A type 1-H / H2A-clustered histone 12 / Histone H2A/s


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
#5: Protein Histone H2A type 1-J / Histone H2A/e


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

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Histone H2B type 1- ... , 2 types, 2 molecules DH

#4: Protein Histone H2B type 1-H / H2B-clustered histone 9 / Histone H2B.j / H2B/j


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
#6: Protein Histone H2B type 1-N / Histone H2B.d / H2B/d


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

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DNA chain , 2 types, 2 molecules IJ

#7: DNA chain DNA (145-MER)


Mass: 44552.379 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#8: DNA chain DNA (145-MER)


Mass: 44961.633 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Non-polymers , 1 types, 1 molecules

#13: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: cGAS-Spsb3-EloBC complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4 / Details: PBS buffer
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20rc2_4400: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 592494 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0076555
ELECTRON MICROSCOPYf_angle_d0.7928824
ELECTRON MICROSCOPYf_dihedral_angle_d4.581864
ELECTRON MICROSCOPYf_chiral_restr0.043959
ELECTRON MICROSCOPYf_plane_restr0.0081129

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