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- PDB-6q2s: Cryo-EM structure of RET/GFRa3/ARTN extracellular complex. The 3D... -
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Basic information
Entry | Database: PDB / ID: 6q2s | ||||||
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Title | Cryo-EM structure of RET/GFRa3/ARTN extracellular complex. The 3D refinement was applied with C2 symmetry. | ||||||
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![]() | SIGNALING PROTEIN / RET / receptor tyrosine kinase / cryo-EM | ||||||
Function / homology | ![]() glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / SUMO is conjugated to E1 (UBA2:SAE1) ...glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / SUMO is conjugated to E1 (UBA2:SAE1) / SUMOylation of nuclear envelope proteins / SUMO is transferred from E1 to E2 (UBE2I, UBC9) / SUMO is proteolytically processed / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / Formation of the ureteric bud / SUMOylation of transcription factors / axon guidance receptor activity / Postmitotic nuclear pore complex (NPC) reformation / SUMOylation of transcription cofactors / positive regulation of neuron maturation / Formation of the nephric duct / enteric nervous system development / SUMOylation of DNA damage response and repair proteins / neuron cell-cell adhesion / SUMOylation of DNA replication proteins / septin ring / sympathetic nervous system development / innervation / induction of positive chemotaxis / peripheral nervous system development / SUMOylation of SUMOylation proteins / plasma membrane protein complex / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / NCAM1 interactions / SUMOylation of RNA binding proteins / positive regulation of cell adhesion mediated by integrin / SUMOylation of chromatin organization proteins / neural crest cell migration / ureteric bud development / response to pain / regulation of axonogenesis / extrinsic component of membrane / ubiquitin-like protein ligase binding / homophilic cell adhesion via plasma membrane adhesion molecules / protein sumoylation / positive regulation of cell size / RET signaling / neuroblast proliferation / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / condensed nuclear chromosome / axon guidance / growth factor activity / neuron migration / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / PML body / positive regulation of neuron projection development / protein tag activity / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / retina development in camera-type eye / nervous system development / signaling receptor activity / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / early endosome / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / external side of plasma membrane / axon / protein phosphorylation / signaling receptor binding / neuronal cell body / calcium ion binding / dendrite / positive regulation of gene expression / positive regulation of DNA-templated transcription / signal transduction / extracellular space / extracellular region / ATP binding / identical protein binding / nucleus / plasma membrane / cytosol Similarity search - Function | ||||||
Biological species | ![]() ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å | ||||||
![]() | Li, J. / Shang, G.J. / Chen, Y.J. / Brautigam, C.A. / Liou, J. / Zhang, X.W. / Bai, X.C. | ||||||
![]() | ![]() Title: Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Authors: Jie Li / Guijun Shang / Yu-Ju Chen / Chad A Brautigam / Jen Liou / Xuewu Zhang / Xiao-Chen Bai / ![]() Abstract: RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ...RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRα1/RET, NRTN/GFRα2/RET and ARTN/GFRα3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRα2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands. | ||||||
History |
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Structure visualization
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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PDBx/mmCIF format | ![]() | 326.9 KB | Display | ![]() |
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PDB format | ![]() | 258.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
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Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 50.7 KB | Display | |
Data in CIF | ![]() | 75.8 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 20579MC ![]() 6q2jC ![]() 6q2nC ![]() 6q2oC ![]() 6q2rC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 25793.287 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Details: A SUMO protein was fused to the N-terminal of NRTN for the protein expression Source: (gene. exp.) ![]() ![]() ![]() Gene: SMT3, ARTN, EVN / Production host: ![]() ![]() #2: Protein | Mass: 38370.023 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #3: Protein | Mass: 69100.812 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P07949, receptor protein-tyrosine kinase #4: Sugar | ChemComp-NAG / #5: Chemical | ChemComp-CA / Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: RET, GFRAL and GDF15 extracellular complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Molecular weight | Value: 200 kDa/nm / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 7.4 |
Specimen | Conc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Details: unspecified |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Calibrated magnification: 46729 X / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 15 sec. / Electron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Num. of grids imaged: 1 |
EM imaging optics | Energyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV |
Image scans | Movie frames/image: 30 / Used frames/image: 1-30 |
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Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114344 / Symmetry type: POINT | ||||||||||||||||||||||||||||||
Atomic model building | B value: 190 / Protocol: FLEXIBLE FIT / Space: REAL |