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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


glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / Peyer's patch morphogenesis / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / enteric nervous system development ...glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / Peyer's patch morphogenesis / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / enteric nervous system development / membrane protein proteolysis / positive regulation of peptidyl-serine phosphorylation of STAT protein / neuron cell-cell adhesion / innervation / nerve development / positive regulation of neuron maturation / plasma membrane protein complex / negative regulation of protein autophosphorylation / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion mediated by integrin / positive regulation of cell size / neural crest cell migration / response to pain / ureteric bud development / regulation of axonogenesis / homophilic cell adhesion via plasma membrane adhesion molecules / regulation of cell adhesion / extrinsic component of membrane / anchored component of membrane / retina development in camera-type eye / cellular response to retinoic acid / positive regulation of neuron projection development / receptor tyrosine kinase binding / receptor protein-tyrosine kinase / transmembrane receptor protein tyrosine kinase activity / growth factor activity / neuron projection development / positive regulation of kinase activity / activation of cysteine-type endopeptidase activity involved in apoptotic process / axon guidance / nervous system development / transmembrane receptor protein tyrosine kinase signaling pathway / positive regulation of MAPK cascade / signaling receptor activity / protein tyrosine kinase activity / activation of MAPK activity / early endosome / endosome membrane / receptor complex / MAPK cascade / multicellular organism development / positive regulation of cell migration / positive regulation of protein kinase B signaling / external side of plasma membrane / membrane raft / axon / neuronal cell body / response to drug / signaling receptor binding / dendrite / protein phosphorylation / calcium ion binding / positive regulation of transcription, DNA-templated / signal transduction / integral component of plasma membrane / extracellular region / ATP binding / plasma membrane
Protein kinase domain / Protein kinase, ATP binding site / Transforming growth factor-beta, C-terminal / Cadherin-like / Glial cell line-derived neurotrophic factor receptor / Glial cell line-derived neurotrophic factor receptor alpha 2 / Tyrosine-protein kinase, active site / Protein kinase-like domain superfamily / Cadherin-like superfamily / GDNF/GAS1 ...Protein kinase domain / Protein kinase, ATP binding site / Transforming growth factor-beta, C-terminal / Cadherin-like / Glial cell line-derived neurotrophic factor receptor / Glial cell line-derived neurotrophic factor receptor alpha 2 / Tyrosine-protein kinase, active site / Protein kinase-like domain superfamily / Cadherin-like superfamily / GDNF/GAS1 / Tyrosine-protein kinase, Ret receptor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Tyrosine-protein kinase, catalytic domain / Cystine-knot cytokine / GDNF receptor alpha / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Ret, cadherin like domain 1 / RET cadherin-like domain 4 / Glial cell line-derived neurotrophic factor family / Serine-threonine/tyrosine-protein kinase, catalytic domain
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 ReportSummary, Full report, XML, About validation report
History
DepositionMay 23, 2018-
Header (metadata) releaseAug 22, 2018-
Map releaseAug 14, 2019-
UpdateDec 18, 2019-
Current statusDec 18, 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
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  • 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
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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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Segmentation: #1

Fileemd_0026_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: Symmetry expanded refinement as C1

Fileemd_0026_additional.map
AnnotationSymmetry expanded refinement as C1
Projections & Slices
AxesZYX

Projections

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Half map: Half map one for consensus refinement map (C2 all bfacauto.mrc)

Fileemd_0026_half_map_1.map
AnnotationHalf map one for consensus refinement map (C2_all_bfacauto.mrc)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Half map two for consensus refinement map (C2 all bfacauto.mrc)

Fileemd_0026_half_map_2.map
AnnotationHalf map two for consensus refinement map (C2_all_bfacauto.mrc)
Projections & Slices
AxesZYX

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Slices (1/2)
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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-2GFRα / 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-2GFRα / 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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