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- EMDB-0026: Neurturin-GFRa2-RET extracellular complex -

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Basic information

Entry
Database: EMDB / ID: EMD-0026
TitleNeurturin-GFRa2-RET extracellular complex
Map data
SampleNeurturin-GFRa2-RET extracellular complex
  • (Neurturin) x 2
  • (GDNF family receptor alpha- ...) x 2
  • (Proto-oncogene tyrosine-protein kinase receptor ...) x 2
Function / homology
Function and homology information


RET signaling / RAF/MAP kinase cascade / NCAM1 interactions / glial cell-derived neurotrophic factor receptor activity / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / positive regulation of metanephric glomerulus development / Peyer's patch morphogenesis / posterior midgut development ...RET signaling / RAF/MAP kinase cascade / NCAM1 interactions / glial cell-derived neurotrophic factor receptor activity / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / positive regulation of metanephric glomerulus development / Peyer's patch morphogenesis / posterior midgut development / enteric nervous system development / ureter maturation / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / innervation / plasma membrane protein complex / neuron cell-cell adhesion / nerve development / positive regulation of neuron maturation / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / negative regulation of protein autophosphorylation / positive regulation of cell adhesion mediated by integrin / neurogenesis / positive regulation of cell size / response to pain / neural crest cell migration / regulation of axonogenesis / ureteric bud development / homophilic cell adhesion via plasma membrane adhesion molecules / regulation of cell adhesion / retina development in camera-type eye / extrinsic component of membrane / anchored component of membrane / cellular response to retinoic acid / positive regulation of neuron projection development / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / neuron projection development / activation of cysteine-type endopeptidase activity involved in apoptotic process / nervous system development / growth factor activity / axon guidance / positive regulation of MAPK cascade / transmembrane receptor protein tyrosine kinase signaling pathway / response to drug / signaling receptor activity / protein tyrosine kinase activity / activation of MAPK activity / receptor complex / early endosome / endosome membrane / MAPK cascade / cell differentiation / positive regulation of cell migration / positive regulation of protein kinase B signaling / membrane raft / external side of plasma membrane / intracellular membrane-bounded organelle / axon / dendrite / neuronal cell body / signaling receptor binding / protein phosphorylation / positive regulation of transcription, DNA-templated / calcium ion binding / integral component of plasma membrane / signal transduction / extracellular region / ATP binding / plasma membrane / cytosol
Glial cell line-derived neurotrophic factor receptor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / RET cadherin-like domain 4 / Ret, cadherin like domain 1 / Glial cell line-derived neurotrophic factor receptor alpha 2 / GDNF receptor alpha / Cystine-knot cytokine / Tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Tyrosine-protein kinase, Ret receptor ...Glial cell line-derived neurotrophic factor receptor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / RET cadherin-like domain 4 / Ret, cadherin like domain 1 / Glial cell line-derived neurotrophic factor receptor alpha 2 / GDNF receptor alpha / Cystine-knot cytokine / Tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Tyrosine-protein kinase, Ret receptor / Cadherin domain / GDNF/GAS1 / Cadherin-like superfamily / Protein kinase-like domain superfamily / Tyrosine-protein kinase, active site / Protein kinase domain / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transforming growth factor-beta, C-terminal / Cadherin-like / Transforming growth factor beta like domain / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / GDNF/GAS1 domain / RET Cadherin like domain 1 / TGF-beta family profile. / Cadherins domain profile. / Protein kinase domain profile. / Tyrosine protein kinases specific active-site signature. / Protein kinases ATP-binding region signature. / RET Cadherin like domain 3 / RET Cadherin like domain 4 / Protein tyrosine kinase
GDNF family receptor alpha-2 / Proto-oncogene tyrosine-protein kinase receptor Ret / Neurturin
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 6.3 Å
AuthorsBigalke JM / Aibara S / Sandmark J / Amunts A
Funding support Sweden, 2 items
OrganizationGrant numberCountry
Knut and Alice Wallenberg Foundation Sweden
Swedish Research CouncilNT_2015-04107 Sweden
CitationJournal: Sci Adv / Year: 2019
Title: Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain.
Authors: Janna M Bigalke / Shintaro Aibara / Robert Roth / Göran Dahl / Euan Gordon / Sarah Dorbéus / A Amunts / Jenny Sandmark /
Abstract: Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details ...Signaling through the receptor tyrosine kinase RET is essential during normal development. Both gain- and loss-of-function mutations are involved in a variety of diseases, yet the molecular details of receptor activation have remained elusive. We have reconstituted the complete extracellular region of the RET signaling complex together with Neurturin (NRTN) and GFRα2 and determined its structure at 5.7-Å resolution by cryo-EM. The proteins form an assembly through RET-GFRα2 and RET-NRTN interfaces. Two key interaction points required for RET extracellular domain binding were observed: (i) the calcium-binding site in RET that contacts GFRα2 domain 3 and (ii) the RET cysteine-rich domain interaction with NRTN. The structure highlights the importance of the RET cysteine-rich domain and allows proposition of a model to explain how complex formation leads to RET receptor dimerization and its activation. This provides a framework for targeting RET activity and for further exploration of mechanisms underlying neurological diseases.
Validation ReportPDB-ID: 6gl7

SummaryFull reportAbout validation report
History
DepositionMay 23, 2018-
Header (metadata) releaseAug 22, 2018-
Map releaseAug 14, 2019-
UpdateAug 21, 2019-
Current statusAug 21, 2019Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0367
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0367
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6gl7
  • Surface level: 0.0367
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_0026.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 400 pix.
= 420. Å
1.05 Å/pix.
x 400 pix.
= 420. Å
1.05 Å/pix.
x 400 pix.
= 420. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density
Contour LevelBy AUTHOR: 0.0367 / Movie #1: 0.0367
Minimum - Maximum-0.033035327 - 0.098938644
Average (Standard dev.)0.0002195305 (±0.002489064)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 419.99997 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.051.051.05
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z420.000420.000420.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0330.0990.000

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Supplemental data

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Mask #1

Fileemd_0026_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire Neurturin-GFRa2-RET extracellular complex

EntireName: Neurturin-GFRa2-RET extracellular complex / Number of components: 7

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Component #1: protein, Neurturin-GFRa2-RET extracellular complex

ProteinName: Neurturin-GFRa2-RET extracellular complex / Recombinant expression: No
MassTheoretical: 254 kDa

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Component #2: protein, Neurturin

ProteinName: Neurturin / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #3: protein, GDNF family receptor alpha-2

ProteinName: GDNF family receptor alpha-2 / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #4: protein, Proto-oncogene tyrosine-protein kinase receptor Ret

ProteinName: Proto-oncogene tyrosine-protein kinase receptor Ret / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #5: protein, Neurturin

ProteinName: Neurturin / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 11.706406 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli (E. coli)

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Component #6: protein, GDNF family receptor alpha-2

ProteinName: GDNF family receptor alpha-2 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 47.635629 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Component #7: protein, Proto-oncogene tyrosine-protein kinase receptor Ret

ProteinName: Proto-oncogene tyrosine-protein kinase receptor Ret / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 68.651352 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Cricetulus griseus (Chinese hamster)

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 38 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 QUANTUM (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C2 (2 fold cyclic) / Number of projections: 186903
3D reconstructionResolution: 6.3 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement protocol: flexible / Refinement space: REAL / Overall bvalue: 220
Output model

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