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- PDB-7sf8: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex wi... -

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Basic information

Entry
Database: PDB / ID: 7sf8
TitleGPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with G protein heterotrimer
Components
  • G protein subunit 13 (Gi2-mini-G13 chimera)
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Isoform 2 of Adhesion G-protein coupled receptor G1
KeywordsMEMBRANE PROTEIN / Adhesion GPCR / GPR56 / ADGRG1 / tethered agonist / stalk / stachel / miniG13 / G13 heterotrimer / G protein / cryoEM
Function / homology
Function and homology information


cerebral cortex regionalization / cerebral cortex radial glia-guided migration / protein kinase C signaling / glial limiting end-foot / negative regulation of neuron migration / hematopoietic stem cell homeostasis / layer formation in cerebral cortex / vascular endothelial growth factor production / positive regulation of neural precursor cell proliferation / extracellular matrix binding ...cerebral cortex regionalization / cerebral cortex radial glia-guided migration / protein kinase C signaling / glial limiting end-foot / negative regulation of neuron migration / hematopoietic stem cell homeostasis / layer formation in cerebral cortex / vascular endothelial growth factor production / positive regulation of neural precursor cell proliferation / extracellular matrix binding / neural precursor cell proliferation / positive regulation of Rho protein signal transduction / seminiferous tubule development / Rho protein signal transduction / collagen binding / positive regulation of cell adhesion / G protein-coupled receptor activity / brain development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / cell migration / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / cell-cell signaling / GTPase binding / heparin binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / angiogenesis / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / cell surface receptor signaling pathway / cell adhesion / G protein-coupled receptor signaling pathway / membrane raft / negative regulation of cell population proliferation / lysosomal membrane / GTPase activity / synapse / protein-containing complex binding / signal transduction / extracellular exosome / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain ...PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / PTX/LNS-Like (PLL) domain / GPCR-Autoproteolysis-INducing (GAIN) subdomain A / GPCR, family 2, orphan receptor, GPR1/GPR3/GPR5 / GAIN domain superfamily / GPCR proteolysis site, GPS, motif / GPS motif / GAIN-B domain profile. / G-protein-coupled receptor proteolytic site domain / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Adhesion G-protein coupled receptor G1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsBarros-Alvarez, X. / Panova, O. / Skiniotis, G.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nature / Year: 2022
Title: The tethered peptide activation mechanism of adhesion GPCRs.
Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B ...Authors: Ximena Barros-Álvarez / Robert M Nwokonko / Alexander Vizurraga / Donna Matzov / Feng He / Makaía M Papasergi-Scott / Michael J Robertson / Ouliana Panova / Eliane Hadas Yardeni / Alpay B Seven / Frank E Kwarcinski / Hongyu Su / Maria Claudia Peroto / Justin G Meyerowitz / Moran Shalev-Benami / Gregory G Tall / Georgios Skiniotis /
Abstract: Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. ...Adhesion G-protein-coupled receptors (aGPCRs) are characterized by the presence of auto-proteolysing extracellular regions that are involved in cell-cell and cell-extracellular matrix interactions. Self cleavage within the aGPCR auto-proteolysis-inducing (GAIN) domain produces two protomers-N-terminal and C-terminal fragments-that remain non-covalently attached after receptors reach the cell surface. Upon dissociation of the N-terminal fragment, the C-terminus of the GAIN domain acts as a tethered agonist (TA) peptide to activate the seven-transmembrane domain with a mechanism that has been poorly understood. Here we provide cryo-electron microscopy snapshots of two distinct members of the aGPCR family, GPR56 (also known as ADGRG1) and latrophilin 3 (LPHN3 (also known as ADGRL3)). Low-resolution maps of the receptors in their N-terminal fragment-bound state indicate that the GAIN domain projects flexibly towards the extracellular space, keeping the encrypted TA peptide away from the seven-transmembrane domain. High-resolution structures of GPR56 and LPHN3 in their active, G-protein-coupled states, reveal that after dissociation of the extracellular region, the decrypted TA peptides engage the seven-transmembrane domain core with a notable conservation of interactions that also involve extracellular loop 2. TA binding stabilizes breaks in the middle of transmembrane helices 6 and 7 that facilitate aGPCR coupling and activation of heterotrimeric G proteins. Collectively, these results enable us to propose a general model for aGPCR activation.
History
DepositionOct 3, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 27, 2022Provider: repository / Type: Initial release
Revision 1.1May 11, 2022Group: 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: Isoform 2 of Adhesion G-protein coupled receptor G1
B: G protein subunit 13 (Gi2-mini-G13 chimera)
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Theoretical massNumber of molelcules
Total (without water)106,6514
Polymers106,6514
Non-polymers00
Water00
1


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

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Components

#1: Protein Isoform 2 of Adhesion G-protein coupled receptor G1 / G-protein coupled receptor 56 / Protein TM7XN1


Mass: 34798.094 Da / Num. of mol.: 1
Fragment: 7TM domain with activation paptide (UNP residues 383-687)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ADGRG1, GPR56, TM7LN4, TM7XN1, UNQ540/PRO1083 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9Y653
#2: Protein G protein subunit 13 (Gi2-mini-G13 chimera)


Mass: 26574.400 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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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: GPR56 (ADGRG1) 7TM domain bound to tethered agonist in complex with mini-G13 protein
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen 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 / Calibrated magnification: 55000 X / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 1.07 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
4cryoSPARC3.2CTF correction
10cryoSPARC3.2initial Euler assignment
11cryoSPARC3.2final Euler assignment
13cryoSPARC3.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 541279 / Symmetry type: POINT

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