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- EMDB-16933: Structure of cGAS in complex with SPSB3-ELOBC -

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Basic information

Entry
Database: EMDB / ID: EMD-16933
TitleStructure of cGAS in complex with SPSB3-ELOBC
Map dataFocused refinement map
Sample
  • Complex: cGAS-Spsb3-EloBC complex
    • Protein or peptide: Cyclic GMP-AMP synthase
    • Protein or peptide: SPRY domain-containing SOCS box protein 3
    • Protein or peptide: Elongin-C
    • Protein or peptide: Elongin-B
  • Ligand: ZINC ION
KeywordscGAS / 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 / cytoplasmic pattern recognition receptor signaling pathway / negative regulation of cGAS/STING signaling pathway / cGMP-mediated signaling / cellular response to exogenous dsRNA / 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 / Formation of HIV-1 elongation complex containing HIV-1 Tat / negative regulation of double-strand break repair via homologous recombination / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / nucleosome binding / positive regulation of defense response to virus by host / RNA Polymerase II Pre-transcription Events / phosphatidylinositol-4,5-bisphosphate binding / activation of innate immune response / cAMP-mediated signaling / transcription corepressor binding / molecular condensate scaffold activity / transcription elongation by RNA polymerase II / determination of adult lifespan / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Vif-mediated degradation of APOBEC3G / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Inactivation of CSF3 (G-CSF) signaling / Evasion by RSV of host interferon responses / Regulation of expression of SLITs and ROBOs / positive regulation of cellular senescence / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / Neddylation / site of double-strand break / ubiquitin-dependent protein catabolic process / protein-containing complex assembly / double-stranded DNA binding / proteasome-mediated ubiquitin-dependent protein catabolic process / defense response to virus / nuclear body / protein ubiquitination / DNA repair / innate immune response / ubiquitin protein ligase binding / DNA damage response / chromatin binding / regulation of transcription by RNA polymerase II / GTP binding / protein homodimerization activity / DNA binding / nucleoplasm / ATP binding / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
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-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 ...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-like, HhH/H2TH-like domain / Mab-21 protein HhH/H2TH-like domain / Mab-21 protein nucleotidyltransferase domain / Mab-21-like / Mab-21 / Elongin B / Elongin-C / 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. / SPRY domain / B30.2/SPRY domain superfamily / Domain in SPla and the RYanodine Receptor. / SKP1/BTB/POZ domain superfamily / 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
Elongin-C / Elongin-B / SPRY domain-containing SOCS box protein 3 / Cyclic GMP-AMP synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.51 Å
AuthorsXu PB / Ablasser A
Funding supportEuropean Union, 1 items
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, 2023-
Header (metadata) releaseFeb 14, 2024-
Map releaseFeb 14, 2024-
UpdateApr 10, 2024-
Current statusApr 10, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16933.png

Downloads & links

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Map

FileDownload / File: emd_16933.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationFocused refinement map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.27 Å/pix.
x 288 pix.
= 365.184 Å		1.27 Å/pix.
x 288 pix.
= 365.184 Å		1.27 Å/pix.
x 288 pix.
= 365.184 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.268 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0987
Minimum - Maximum-0.21727766 - 0.71860415
Average (Standard dev.)0.0005619882 (±0.013853456)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 365.184 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: DeepEMhancer processed map

Fileemd_16933_additional_1.map
AnnotationDeepEMhancer processed map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: sharpened map with b-factor -127.4

Fileemd_16933_additional_2.map
Annotationsharpened map with b-factor -127.4
Projections & Slices
AxesZYX

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_16933_half_map_1.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_16933_half_map_2.map
Projections & Slices
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Sample components

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Entire : cGAS-Spsb3-EloBC complex

EntireName: cGAS-Spsb3-EloBC complex
Components
  • Complex: cGAS-Spsb3-EloBC complex
    • Protein or peptide: Cyclic GMP-AMP synthase
    • Protein or peptide: SPRY domain-containing SOCS box protein 3
    • Protein or peptide: Elongin-C
    • Protein or peptide: Elongin-B
  • Ligand: ZINC ION

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Supramolecule #1: cGAS-Spsb3-EloBC complex

SupramoleculeName: cGAS-Spsb3-EloBC complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Cyclic GMP-AMP synthase

MacromoleculeName: Cyclic GMP-AMP synthase / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: cyclic GMP-AMP synthase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.714145 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: RDAAPGASKL RAVLEKLKLS RDDISTAAGM VKGVVDHLLL RLKCDSAFRG VGLLNTGSYY EHVKISAPNE FDVMFKLEVP RIQLEEYSN TRAYYFVKFK RNPKENPLSQ FLEGEILSAS KMLSKFRKII AEEINDIKDT DVIMKAKRGG SPAVTLLISE K ISVDITLA ...String:
RDAAPGASKL RAVLEKLKLS RDDISTAAGM VKGVVDHLLL RLKCDSAFRG VGLLNTGSYY EHVKISAPNE FDVMFKLEVP RIQLEEYSN TRAYYFVKFK RNPKENPLSQ FLEGEILSAS KMLSKFRKII AEEINDIKDT DVIMKAKRGG SPAVTLLISE K ISVDITLA LESKSSWPAS TQEGLRIQNW LSAKVRKQLR LKPFYLVPKH AKEGNGFQEE TWRLSFSHIE KEILNNHGKS KT CCENKEE KCCRKDCLKL MKYLLEQLKE RFKDKAHLDK FSSYHVKTAF FHVCTQNPQD SQWDRKDLGL CFDNCVTYFL QCL RTEKLE NYFIPEFNLF SSNLIDKRSK EFLTKQIEYE RNNEFPVFDE F

UniProtKB: Cyclic GMP-AMP synthase

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Macromolecule #2: SPRY domain-containing SOCS box protein 3

MacromoleculeName: SPRY domain-containing SOCS box protein 3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 27.41524 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SSLHSAHRGR DCRCGEEDEY FDWVWDDLNK SSATLLSCDN RKVSFHMEYS CGTAAIRGTK ELGEGQHFWE IKMTSPVYGT DMMVGIGTS DVDLDKYRHT FCSLLGRDED SWGLSYTGLL HHKGDKTSFS SRFGQGSIIG VHLDTWHGTL TFFKNRKCIG V AATKLQNK ...String:
SSLHSAHRGR DCRCGEEDEY FDWVWDDLNK SSATLLSCDN RKVSFHMEYS CGTAAIRGTK ELGEGQHFWE IKMTSPVYGT DMMVGIGTS DVDLDKYRHT FCSLLGRDED SWGLSYTGLL HHKGDKTSFS SRFGQGSIIG VHLDTWHGTL TFFKNRKCIG V AATKLQNK RFYPMVCSTA ARSSMKVTRS CASATSLQYL CCHRLRQLRP DSGDTLEGLP LPPGLKQVLH NKLGWVLSMS CS RRKA

UniProtKB: SPRY domain-containing SOCS box protein 3

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Macromolecule #3: Elongin-C

MacromoleculeName: Elongin-C / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.485135 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MDGEEKTYGG CEGPDAMYVK LISSDGHEFI VKREHALTSG TIKAMLSGPG QFAENETNEV NFREIPSHVL SKVCMYFTYK VRYTNSSTE IPEFPIAPEI ALELLMAANF LDC

UniProtKB: Elongin-C

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Macromolecule #4: Elongin-B

MacromoleculeName: Elongin-B / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.147781 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
MDVFLMIRRH KTTIFTDAKE SSTVFELKRI VEGILKRPPD EQRLYKDDQL LDDGKTLGEC GFTSQTARPQ APATVGLAFR ADDTFEALC IEPFSSPPEL PDVMKPQDSG SSANEQAVQ

UniProtKB: Elongin-B

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Macromolecule #5: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4 / Details: PBS buffer
GridModel: C-flat-2/2 / Material: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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

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Image processing

Startup modelType of model: INSILICO MODEL
In silico model: alphafold2 prediction of individual proteins
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.51 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 592494
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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