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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 dataConsensus refinement with C2 symmetry applied.
Sample
  • Complex: Neurturin-GFRa2-RET extracellular complex
    • Complex: Neurturin
      • Protein or peptide: Neurturin
    • Complex: GDNF family receptor alpha-2
      • Protein or peptide: GDNF family receptor alpha-2
    • Complex: Proto-oncogene tyrosine-protein kinase receptor Ret
      • Protein or peptide: Proto-oncogene tyrosine-protein kinase receptor Ret
Function / homology
Function and homology information


glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development ...glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / posterior midgut development / positive regulation of peptidyl-serine phosphorylation of STAT protein / membrane protein proteolysis / Formation of the ureteric bud / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / nerve development / innervation / plasma membrane protein complex / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / heparan sulfate binding / NCAM1 interactions / positive regulation of cell adhesion mediated by integrin / ureteric bud development / neural crest cell migration / extrinsic component of membrane / regulation of axonogenesis / response to pain / homophilic cell adhesion via plasma membrane adhesion molecules / RET signaling / positive regulation of cell size / regulation of cell adhesion / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / axon guidance / growth factor activity / receptor protein-tyrosine kinase / : / receptor tyrosine kinase binding / positive regulation of neuron projection development / neuron projection development / MAPK cascade / retina development in camera-type eye / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / protein tyrosine kinase activity / positive regulation of MAPK cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / positive regulation of cell migration / response to xenobiotic stimulus / protein phosphorylation / axon / external side of plasma membrane / signaling receptor binding / neuronal cell body / dendrite / calcium ion binding / positive regulation of gene expression / positive regulation of DNA-templated transcription / signal transduction / extracellular space / extracellular region / ATP binding / plasma membrane
Similarity search - Function
Glial cell line-derived neurotrophic factor receptor alpha 2 / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / Glial cell line-derived neurotrophic factor family / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Tyrosine-protein kinase, Ret receptor / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 ...Glial cell line-derived neurotrophic factor receptor alpha 2 / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Glial cell line-derived neurotrophic factor receptor / GDNF receptor alpha / Glial cell line-derived neurotrophic factor family / 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 / RET, Cysteine Rich Domain / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Cadherin domain / Cadherin-like / Cadherins domain profile. / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
GDNF family receptor alpha-2 / Proto-oncogene tyrosine-protein kinase receptor Ret / Neurturin
Similarity search - Component
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.
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

Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_0026.png

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)
AnnotationConsensus refinement with C2 symmetry applied.
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

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 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 °

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Supplemental data

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Mask #1

Fileemd_0026_msk_1.map
Projections & Slices
AxesZYX

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Additional map: Symmetry expanded refinement as C1

Fileemd_0026_additional.map
AnnotationSymmetry expanded refinement as C1
Projections & Slices
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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

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Slices (1/2)
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Histogram

Histogram (log scale)

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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
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Sample components

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Entire : Neurturin-GFRa2-RET extracellular complex

EntireName: Neurturin-GFRa2-RET extracellular complex
Components
  • Complex: Neurturin-GFRa2-RET extracellular complex
    • Complex: Neurturin
      • Protein or peptide: Neurturin
    • Complex: GDNF family receptor alpha-2
      • Protein or peptide: GDNF family receptor alpha-2
    • Complex: Proto-oncogene tyrosine-protein kinase receptor Ret
      • Protein or peptide: Proto-oncogene tyrosine-protein kinase receptor Ret

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Supramolecule #1: Neurturin-GFRa2-RET extracellular complex

SupramoleculeName: Neurturin-GFRa2-RET extracellular complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 254 KDa

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Supramolecule #2: Neurturin

SupramoleculeName: Neurturin / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Supramolecule #3: GDNF family receptor alpha-2

SupramoleculeName: GDNF family receptor alpha-2 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Supramolecule #4: Proto-oncogene tyrosine-protein kinase receptor Ret

SupramoleculeName: Proto-oncogene tyrosine-protein kinase receptor Ret / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Macromolecule #1: Neurturin

MacromoleculeName: Neurturin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.706406 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ARLGARPCGL RELEVRVSEL GLGYASDETV LFRYCAGACE AAARVYDLGL RRLRQRRRLR RERVRAQPCC RPTAYEDEVS FLDAHSRYH TVHELSAREC ACV

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Macromolecule #2: GDNF family receptor alpha-2

MacromoleculeName: GDNF family receptor alpha-2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.635629 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: SPSSLQGPEL HGWRPPVDCV RANELCAAES NCSSRYRTLR QCLAGRDRNT MLANKECQAA LEVLQESPLY DCRCKRGMKK ELQCLQIYW SIHLGLTEGE EFYEASPYEP VTSRLSDIFR LASIFSGTGA DPVVSAKSNH CLDAAKACNL NDNCKKLRSS Y ISICNREI ...String:
SPSSLQGPEL HGWRPPVDCV RANELCAAES NCSSRYRTLR QCLAGRDRNT MLANKECQAA LEVLQESPLY DCRCKRGMKK ELQCLQIYW SIHLGLTEGE EFYEASPYEP VTSRLSDIFR LASIFSGTGA DPVVSAKSNH CLDAAKACNL NDNCKKLRSS Y ISICNREI SPTERCNRRK CHKALRQFFD RVPSEYTYRM LFCSCQDQAC AERRRQTILP SCSYEDKEKP NCLDLRGVCR TD HLCRSRL ADFHANCRAS YQTVTSCPAD NYQACLGSYA GMIGFDMTPN YVDSSPTGIV VSPWCSCRGS GNMEEECEKF LRD FTENPC LRNAIQAFGN GTDVNVSPKG PSFQATQAPR VEKTPSLPDD LSDSTSLGTS VITTCTSVQE QGLKANNSKE LSMC FTELT TNIIPGSNKV IKPNSHHHHH H

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Macromolecule #3: Proto-oncogene tyrosine-protein kinase receptor Ret

MacromoleculeName: Proto-oncogene tyrosine-protein kinase receptor Ret / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 68.651352 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: LYFSRDAYWE KLYVDQAAGT PLLYVHALRD APEEVPSFRL GQHLYGTYRT RLHENNWICI QEDTGLLYLN RSLDHSSWEK LSVRNRGFP LLTVYLKVFL SPTSLREGEC QWPGCARVYF SFFNTSFPAC SSLKPRELCF PETRPSFRIR ENRPPGTFHQ F RLLPVQFL ...String:
LYFSRDAYWE KLYVDQAAGT PLLYVHALRD APEEVPSFRL GQHLYGTYRT RLHENNWICI QEDTGLLYLN RSLDHSSWEK LSVRNRGFP LLTVYLKVFL SPTSLREGEC QWPGCARVYF SFFNTSFPAC SSLKPRELCF PETRPSFRIR ENRPPGTFHQ F RLLPVQFL CPNISVAYRL LEGEGLPFRC APDSLEVSTR WALDREQREK YELVAVCTVH AGAREEVVMV PFPVTVYDED DS APTFPAG VDTASAVVEF KRKEDTVVAT LRVFDADVVP ASGELVRRYT STLLPGDTWA QQTFRVEHWP NETSVQANGS FVR ATVHDY RLVLNRNLSI SENRTMQLAV LVNDSDFQGP GAGVLLLHFN VSVLPVSLHL PSTYSLSVSR RARRFAQIGK VCVE NCQAF SGINVQYKLH SSGANCSTLG VVTSAEDTSG ILFVNDTKAL RRPKCAELHY MVVATDQQTS RQAQAQLLVT VEGSY VAEE AGCPLSCAVS KRRLECEECG GLGSPTGRCE WRQGDGKGIT RNFSTCSPST KTCPDGHCDV VETQDINICP QDCLRG SIV GGHEPGEPRG IKAGYGTCNC FPEEEKCFCE PEDIQDPLCD ELCRENLYFQ

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 38.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 6.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 186903
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 220
Output model

PDB-6gl7:
Neurturin-GFRa2-RET extracellular complex

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