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- PDB-6nt7: Cryo-EM structure of full-length chicken STING in the cGAMP-bound... -

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Entry
Database: PDB / ID: 6nt7
TitleCryo-EM structure of full-length chicken STING in the cGAMP-bound dimeric state
ComponentsStimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / ER / membrane / adaptor
Function / homology
Function and homology information


STING mediated induction of host immune responses / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / cGAS/STING signaling pathway / reticulophagy / protein complex oligomerization / positive regulation of macroautophagy / autophagosome membrane / autophagosome assembly ...STING mediated induction of host immune responses / 2',3'-cyclic GMP-AMP binding / proton channel activity / cyclic-di-GMP binding / cGAS/STING signaling pathway / reticulophagy / protein complex oligomerization / positive regulation of macroautophagy / autophagosome membrane / autophagosome assembly / positive regulation of type I interferon production / activation of innate immune response / positive regulation of interferon-beta production / endoplasmic reticulum-Golgi intermediate compartment membrane / autophagosome / Neutrophil degranulation / cytoplasmic vesicle / defense response to virus / Golgi membrane / innate immune response / endoplasmic reticulum membrane / perinuclear region of cytoplasm / protein homodimerization activity / cytoplasm
Similarity search - Function
: / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / Transmembrane protein 173
Similarity search - Domain/homology
cGAMP / Stimulator of interferon genes protein / Stimulator of interferon genes protein
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsShang, G. / Zhang, C. / Chen, Z.J. / Bai, X. / Zhang, X.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM088197 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM130289 United States
Howard Hughes Medical Institute (HHMI) United States
Welch FoundationI-1389 United States
Welch FoundationI-1702 United States
Welch FoundationI-1944 United States
CitationJournal: Nature / Year: 2019
Title: Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP.
Authors: Guijun Shang / Conggang Zhang / Zhijian J Chen / Xiao-Chen Bai / Xuewu Zhang /
Abstract: Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds ...Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS). STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
History
DepositionJan 28, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 6, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Apr 3, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]
Revision 1.5Mar 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Stimulator of interferon genes protein
B: Stimulator of interferon genes protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)89,0893
Polymers88,4142
Non-polymers6741
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: assay for oligomerization
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Stimulator of interferon genes protein


Mass: 44207.070 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: TMEM173 / Production host: Homo sapiens (human) / References: UniProt: A0A1D5P7Q9, UniProt: E1C7U0*PLUS
#2: Chemical ChemComp-1SY / cGAMP / 2',3' cGAMP / c-GMP-AMP / c[G(2',5')pA(3',5')p]


Mass: 674.411 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H24N10O13P2 / Feature type: SUBJECT OF INVESTIGATION

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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: full-length chicken STING / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Gallus gallus (chicken)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK293 GnTI-
Buffer solutionpH: 8
SpecimenConc.: 4.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 40 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV
Image scansMovie frames/image: 20

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Processing

EM software
IDNameCategory
1RELIONparticle selection
4GctfCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 156804 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL

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