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- EMDB-20573: Cryo-EM structure of RET/GFRAL/GDF15 extracellular complex. The 3... -

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Basic information

Entry
Database: EMDB / ID: EMD-20573
TitleCryo-EM structure of RET/GFRAL/GDF15 extracellular complex. The 3D refinement was focused on one of two halves with C1 symmetry applied.
Map dataCryo-EM structure of RET/GFRAL/GDF15 extracellular complex. The 3D refinement was focused on one of two halves with C1 symmetry allied.
Sample
  • Complex: RET, GFRAL and GDF15 extracellular complex
Function / homology
Function and homology information


negative regulation of growth hormone receptor signaling pathway / glial cell-derived neurotrophic factor receptor activity / reduction of food intake in response to dietary excess / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / glial cell-derived neurotrophic factor receptor signaling pathway / posterior midgut development / ureter maturation / embryonic epithelial tube formation / lymphocyte migration into lymphoid organs ...negative regulation of growth hormone receptor signaling pathway / glial cell-derived neurotrophic factor receptor activity / reduction of food intake in response to dietary excess / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / glial cell-derived neurotrophic factor receptor signaling pathway / posterior midgut development / ureter maturation / embryonic epithelial tube formation / lymphocyte migration into lymphoid organs / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / positive regulation of neuron maturation / neuron cell-cell adhesion / enteric nervous system development / innervation / plasma membrane protein complex / neuron maturation / SMAD protein signal transduction / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / neural crest cell migration / ureteric bud development / negative regulation of multicellular organism growth / response to pain / regulation of axonogenesis / stress-activated protein kinase signaling cascade / positive regulation of myoblast fusion / homophilic cell adhesion via plasma membrane adhesion molecules / positive regulation of cell size / RET signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / transforming growth factor beta receptor signaling pathway / cytokine activity / axon guidance / growth factor activity / receptor protein-tyrosine kinase / receptor tyrosine kinase binding / positive regulation of neuron projection development / cell surface receptor protein tyrosine kinase signaling pathway / activation of cysteine-type endopeptidase activity involved in apoptotic process / MAPK cascade / actin cytoskeleton / cell-cell signaling / retina development in camera-type eye / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / early endosome / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / axon / external side of plasma membrane / protein phosphorylation / focal adhesion / neuronal cell body / dendrite / calcium ion binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / Golgi apparatus / signal transduction / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / RET Cadherin like domain 1 ...Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET, cadherin-like domain 4 / RET Cadherin like domain 1 / RET Cadherin like domain 3 / RET Cadherin like domain 4 / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cadherin domain / Cadherins domain profile. / Cadherin-like / Cadherin-like superfamily / Cystine-knot cytokine / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Proto-oncogene tyrosine-protein kinase receptor Ret / GDNF family receptor alpha-like / Growth/differentiation factor 15
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLi J / Shang GJ / Zhang XW / Bai XC
CitationJournal: Elife / Year: 2019
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
DepositionAug 8, 2019-
Header (metadata) releaseOct 2, 2019-
Map releaseOct 2, 2019-
UpdateOct 2, 2019-
Current statusOct 2, 2019Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.052
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.052
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20573.png

Downloads & links

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Map

FileDownload / File: emd_20573.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of RET/GFRAL/GDF15 extracellular complex. The 3D refinement was focused on one of two halves with C1 symmetry allied.
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.052 / Movie #1: 0.052
Minimum - Maximum-0.21691476 - 0.3202552
Average (Standard dev.)0.00016042714 (±0.006974563)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 256.80002 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z256.800256.800256.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.2170.3200.000

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Supplemental data

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Sample components

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Entire : RET, GFRAL and GDF15 extracellular complex

EntireName: RET, GFRAL and GDF15 extracellular complex
Components
  • Complex: RET, GFRAL and GDF15 extracellular complex

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Supramolecule #1: RET, GFRAL and GDF15 extracellular complex

SupramoleculeName: RET, GFRAL and GDF15 extracellular complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
Molecular weightTheoretical: 200 kDa/nm

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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

Concentration1 mg/mL
BufferpH: 7.4
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 46729 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-30 / Number grids imaged: 1 / Average exposure time: 15.0 sec. / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: RELION
Startup modelType of model: OTHER / Details: The initial model was generated in RELION.
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 520480

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 190

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