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- PDB-7r4h: phospho-STING binding to adaptor protein complex-1 -

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Basic information

Entry
Database: PDB / ID: 7r4h
Titlephospho-STING binding to adaptor protein complex-1
Components
  • (AP-1 complex subunit ...) x 4
  • ADP-ribosylation factor 1
  • Stimulator of interferon genes protein
KeywordsIMMUNE SYSTEM / STING / innate immunity / TGN / AP-1
Function / homology
Function and homology information


basolateral protein secretion / endosome to melanosome transport / Lysosome Vesicle Biogenesis / AP-1 adaptor complex / mitotic cleavage furrow ingression / trans-Golgi Network Vesicle Budding / platelet dense granule organization / Glycosphingolipid transport / melanosome assembly / regulation of receptor internalization ...basolateral protein secretion / endosome to melanosome transport / Lysosome Vesicle Biogenesis / AP-1 adaptor complex / mitotic cleavage furrow ingression / trans-Golgi Network Vesicle Budding / platelet dense granule organization / Glycosphingolipid transport / melanosome assembly / regulation of receptor internalization / STING complex / Intra-Golgi traffic / regulation of Arp2/3 complex-mediated actin nucleation / STAT6-mediated induction of chemokines / Golgi Associated Vesicle Biogenesis / Synthesis of PIPs at the Golgi membrane / protein localization to endoplasmic reticulum / clathrin adaptor activity / 2',3'-cyclic GMP-AMP binding / cyclic-di-GMP binding / MHC class II antigen presentation / STING mediated induction of host immune responses / serine/threonine protein kinase complex / Nef Mediated CD4 Down-regulation / positive regulation of type I interferon-mediated signaling pathway / IRF3-mediated induction of type I IFN / dendritic spine organization / cGAS/STING signaling pathway / long-term synaptic depression / determination of left/right symmetry / proton channel activity / clathrin-coated vesicle / pattern recognition receptor signaling pathway / reticulophagy / COPI-dependent Golgi-to-ER retrograde traffic / clathrin binding / Lysosome Vesicle Biogenesis / cytoplasmic pattern recognition receptor signaling pathway / Golgi Associated Vesicle Biogenesis / cellular response to exogenous dsRNA / Synthesis of PIPs at the plasma membrane / cell leading edge / protein complex oligomerization / autophagosome membrane / positive regulation of macroautophagy / intracellular copper ion homeostasis / autophagosome assembly / positive regulation of type I interferon production / protein targeting / positive regulation of DNA-binding transcription factor activity / cellular response to interferon-beta / COPI-mediated anterograde transport / vesicle-mediated transport / positive regulation of defense response to virus by host / clathrin-coated pit / signaling adaptor activity / Neutrophil degranulation / antiviral innate immune response / endoplasmic reticulum-Golgi intermediate compartment membrane / MHC class II antigen presentation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / activation of innate immune response / Regulation of innate immune responses to cytosolic DNA / protein serine/threonine kinase binding / positive regulation of interferon-beta production / autophagosome / cytoplasmic vesicle membrane / secretory granule membrane / Nef mediated downregulation of MHC class I complex cell surface expression / sarcomere / trans-Golgi network membrane / small monomeric GTPase / intracellular protein transport / kidney development / trans-Golgi network / cellular response to virus / SARS-CoV-1 activates/modulates innate immune responses / synaptic vesicle / peroxisome / presynapse / heart development / regulation of inflammatory response / defense response to virus / DNA-binding transcription factor binding / RNA polymerase II-specific DNA-binding transcription factor binding / mitochondrial outer membrane / early endosome / neuron projection / endosome / postsynaptic density / cilium / ciliary basal body / Golgi membrane / protein domain specific binding / lysosomal membrane / innate immune response / focal adhesion / intracellular membrane-bounded organelle / GTPase activity / synapse
Similarity search - Function
Beta-Lactamase - #60 / Mu homology domain, subdomain B / AP-1 complex subunit sigma / Adaptor protein complex AP-1, gamma subunit / Gamma-adaptin ear (GAE) domain / Gamma-adaptin ear (GAE) domain profile. / Clathrin adaptor, beta-adaptin, appendage, Ig-like subdomain / Beta2-adaptin appendage, C-terminal sub-domain / AP-1/2/4 complex subunit beta / Adaptor protein complex, sigma subunit ...Beta-Lactamase - #60 / Mu homology domain, subdomain B / AP-1 complex subunit sigma / Adaptor protein complex AP-1, gamma subunit / Gamma-adaptin ear (GAE) domain / Gamma-adaptin ear (GAE) domain profile. / Clathrin adaptor, beta-adaptin, appendage, Ig-like subdomain / Beta2-adaptin appendage, C-terminal sub-domain / AP-1/2/4 complex subunit beta / Adaptor protein complex, sigma subunit / : / Beta-adaptin appendage, C-terminal subdomain / Beta2-adaptin appendage, C-terminal sub-domain / ADP-ribosylation factor 1-5 / AP complex subunit beta / Clathrin adaptor complex, small chain / Clathrin adaptor complexes small chain signature. / Clathrin adaptor complexes medium chain signature 1. / Clathrin adaptor, mu subunit / Clathrin adaptor, mu subunit, conserved site / Clathrin adaptor complexes medium chain signature 2. / : / Coatomer/calthrin adaptor appendage, C-terminal subdomain / Clathrin adaptor, alpha/beta/gamma-adaptin, appendage, Ig-like subdomain / Adaptin C-terminal domain / Adaptin C-terminal domain / : / STING transmembrane domain / : / : / Stimulator of interferon genes protein / Stimulator of interferon genes protein, C-terminal domain superfamily / STING ligand-binding domain / AP complex, mu/sigma subunit / Adaptor complexes medium subunit family / Clathrin adaptor complex small chain / Clathrin/coatomer adaptor, adaptin-like, N-terminal / Adaptin N terminal region / AP-2 complex subunit mu, C-terminal superfamily / Mu homology domain / Mu homology domain (MHD) profile. / Clathrin adaptor, appendage, Ig-like subdomain superfamily / Small GTPase superfamily, ARF type / Small GTPase Arf domain profile. / Sar1p-like members of the Ras-family of small GTPases / Small GTPase superfamily, ARF/SAR type / ADP-ribosylation factor family / Longin-like domain superfamily / ARF-like small GTPases; ARF, ADP-ribosylation factor / TBP domain superfamily / Armadillo/beta-catenin-like repeats / Armadillo / Leucine-rich Repeat Variant / Leucine-rich Repeat Variant / Beta-Lactamase / Rab subfamily of small GTPases / Armadillo-like helical / Alpha Horseshoe / Small GTP-binding protein domain / Armadillo-type fold / Immunoglobulin-like / Sandwich / P-loop containing nucleoside triphosphate hydrolase / 2-Layer Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
GUANOSINE-5'-TRIPHOSPHATE / AP-1 complex subunit gamma-1 / AP-1 complex subunit mu-1 / ADP-ribosylation factor 1 / AP-1 complex subunit beta-1 / Stimulator of interferon genes protein / AP-1 complex subunit sigma-3
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.34 Å
AuthorsXu, P. / Ablasser, A.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Molecular Biology Organization (EMBO)ALTF-184European Union
CitationJournal: Nature / Year: 2022
Title: Clathrin-associated AP-1 controls termination of STING signalling.
Authors: Ying Liu / Pengbiao Xu / Sophie Rivara / Chong Liu / Jonathan Ricci / Xuefeng Ren / James H Hurley / Andrea Ablasser /
Abstract: Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate ...Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate immunity during infection, cancer and immunotherapy. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction. The mechanism that ends STING signalling at the Golgi remains unknown. Here we show that adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation. We find that AP-1 sorts phosphorylated STING into clathrin-coated transport vesicles for delivery to the endolysosomal system, where STING is degraded. We identify a highly conserved dileucine motif in the cytosolic C-terminal tail (CTT) of STING that, together with TBK1-dependent CTT phosphorylation, dictates the AP-1 engagement of STING. A cryo-electron microscopy structure of AP-1 in complex with phosphorylated STING explains the enhanced recognition of TBK1-activated STING. We show that suppression of AP-1 exacerbates STING-induced immune responses. Our results reveal a structural mechanism of negative regulation of STING and establish that the initiation of signalling is inextricably associated with its termination to enable transient activation of immunity.
History
DepositionFeb 8, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 14, 2022Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: AP-1 complex subunit beta-1
C: ADP-ribosylation factor 1
G: AP-1 complex subunit gamma-1
H: ADP-ribosylation factor 1
L: Stimulator of interferon genes protein
M: AP-1 complex subunit mu-1
S: AP-1 complex subunit sigma-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)240,36911
Polymers239,2747
Non-polymers1,0954
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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AP-1 complex subunit ... , 4 types, 4 molecules BGMS

#1: Protein AP-1 complex subunit beta-1 / Adaptor protein complex AP-1 subunit beta-1 / Adaptor-related protein complex 1 subunit beta-1 / ...Adaptor protein complex AP-1 subunit beta-1 / Adaptor-related protein complex 1 subunit beta-1 / Beta-1-adaptin / Beta-adaptin 1 / Clathrin assembly protein complex 1 beta large chain / Golgi adaptor HA1/AP1 adaptin beta subunit


Mass: 66008.422 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AP1B1, ADTB1, BAM22, CLAPB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q10567
#3: Protein AP-1 complex subunit gamma-1 / Adaptor protein complex AP-1 subunit gamma-1 / Adaptor-related protein complex 1 subunit gamma-1 / ...Adaptor protein complex AP-1 subunit gamma-1 / Adaptor-related protein complex 1 subunit gamma-1 / Clathrin assembly protein complex 1 gamma-1 large chain / Gamma-adaptin / Gamma1-adaptin / Golgi adaptor HA1/AP1 adaptin subunit gamma-1


Mass: 67399.242 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ap1g1, Adtg, Clapg1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P22892
#5: Protein AP-1 complex subunit mu-1 / AP-mu chain family member mu1A / Adaptor protein complex AP-1 subunit mu-1 / Adaptor-related ...AP-mu chain family member mu1A / Adaptor protein complex AP-1 subunit mu-1 / Adaptor-related protein complex 1 subunit mu-1 / Clathrin assembly protein complex 1 mu-1 medium chain 1 / Clathrin coat assembly protein AP47 / Clathrin coat-associated protein AP47 / Golgi adaptor HA1/AP1 adaptin mu-1 subunit / Mu-adaptin 1 / Mu1A-adaptin


Mass: 48606.730 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Ap1m1, Cltnm / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P35585
#6: Protein AP-1 complex subunit sigma-3 / Adaptor protein complex AP-1 subunit sigma-1C / Adaptor-related protein complex 1 subunit sigma-1C ...Adaptor protein complex AP-1 subunit sigma-1C / Adaptor-related protein complex 1 subunit sigma-1C / Clathrin assembly protein complex 1 sigma-1C small chain / Golgi adaptor HA1/AP1 adaptin sigma-1C subunit / Sigma 1C subunit of AP-1 clathrin / Sigma-adaptin 1C / Sigma1C-adaptin


Mass: 18321.338 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AP1S3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q96PC3

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Protein / Protein/peptide , 2 types, 3 molecules CHL

#2: Protein ADP-ribosylation factor 1


Mass: 18936.600 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ARF1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P84077
#4: Protein/peptide Stimulator of interferon genes protein / hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / ...hSTING / Endoplasmic reticulum interferon stimulator / ERIS / Mediator of IRF3 activation / hMITA / Transmembrane protein 173


Mass: 1065.068 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: phospho-STING tail / Source: (gene. exp.) Homo sapiens (human) / Gene: STING1, ERIS, MITA, STING, TMEM173 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q86WV6

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Non-polymers , 2 types, 4 molecules

#7: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: phospho-STING binding to adaptor protein complex-1 / Type: COMPLEX / Entity ID: #1-#6 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.4 / Details: PBS buffer
Buffer component
IDConc.NameFormulaBuffer-ID
1137 mMsodium chlorideNaCl1
22.7 mMpotassium chlorideKCl1
310 mMSodium phosphate dibasicNa2HPO41
41.8 mMPotassium Phosphate, MonobasicKH2PO41
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 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
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 322238 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00616767
ELECTRON MICROSCOPYf_angle_d1.21322686
ELECTRON MICROSCOPYf_dihedral_angle_d9.5372259
ELECTRON MICROSCOPYf_chiral_restr0.062621
ELECTRON MICROSCOPYf_plane_restr0.0092870

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