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

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Basic information

Entry
Database: PDB / ID: 6gl7
TitleNeurturin-GFRa2-RET extracellular complex
Components
  • GDNF family receptor alpha-2GFRα
  • Neurturin
  • Proto-oncogene tyrosine-protein kinase receptor Ret
KeywordsSIGNALING PROTEIN / Neurotrophic signalling / Receptor tyrosine kinase / GDNF family of ligands
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
RET Cadherin like domain 4 / GDNF receptor alpha / Glial cell line-derived neurotrophic factor receptor alpha 2 / Cadherin-like superfamily / GDNF/GAS1 / Tyrosine-protein kinase, Ret receptor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Protein kinase, ATP binding site / Glial cell line-derived neurotrophic factor receptor / Cadherin-like ...RET Cadherin like domain 4 / GDNF receptor alpha / Glial cell line-derived neurotrophic factor receptor alpha 2 / Cadherin-like superfamily / GDNF/GAS1 / Tyrosine-protein kinase, Ret receptor / Glial cell line-derived neurotrophic factor receptor, alpha 1/2 / Protein kinase, ATP binding site / Glial cell line-derived neurotrophic factor receptor / Cadherin-like / Tyrosine-protein kinase, catalytic domain / Cystine-knot cytokine / Tyrosine-protein kinase receptor Ret, cadherin like domain 3 / Tyrosine-protein kinase, active site / Ret, cadherin like domain 1 / RET cadherin-like domain 4 / Glial cell line-derived neurotrophic factor family / Transforming growth factor beta like domain / GDNF/GAS1 domain / Cadherin domain / RET Cadherin like domain 1 / Transforming growth factor-beta, C-terminal / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase domain / RET Cadherin like domain 3 / Protein kinase-like domain superfamily
Proto-oncogene tyrosine-protein kinase receptor Ret / Neurturin / GDNF family receptor alpha-2
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.3 Å
AuthorsBigalke, J.M. / Aibara, S. / Sandmark, J. / Amunts, A.
Funding support Sweden, 5items
OrganizationGrant numberCountry
FFL15:0325 Sweden
Knut and Alice Wallenberg Foundation Sweden
M44/16 Sweden
Swedish Research CouncilNT_2015-04107 Sweden
CAN 2017/1041 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 Report
SummaryFull reportAbout validation report
History
DepositionMay 23, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Dec 18, 2019Group: Other / Category: atom_sites
Item: _atom_sites.fract_transf_matrix[1][1] / _atom_sites.fract_transf_matrix[2][2] / _atom_sites.fract_transf_matrix[3][3]

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Assembly

Deposited unit
B: Neurturin
D: GDNF family receptor alpha-2
A: Neurturin
C: GDNF family receptor alpha-2
F: Proto-oncogene tyrosine-protein kinase receptor Ret
E: Proto-oncogene tyrosine-protein kinase receptor Ret


Theoretical massNumber of molelcules
Total (without water)255,9876
Polymers255,9876
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, surface plasmon resonance
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TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10460 Å2
ΔGint-5 kcal/mol
Surface area82960 Å2
MethodPISA

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Components

#1: Protein Neurturin /


Mass: 11706.406 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRTN / Production host: Escherichia coli (E. coli) / References: UniProt: Q99748
#2: Protein GDNF family receptor alpha-2 / GFRα / GFR-alpha-2 / GDNF receptor beta / GDNFR-beta / Neurturin receptor alpha / NTNR-alpha / RET ligand ...GFR-alpha-2 / GDNF receptor beta / GDNFR-beta / Neurturin receptor alpha / NTNR-alpha / RET ligand 2 / TGF-beta-related neurotrophic factor receptor 2


Mass: 47635.629 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GFRA2, GDNFRB, RETL2, TRNR2 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: O00451
#3: Protein Proto-oncogene tyrosine-protein kinase receptor Ret / Cadherin family member 12 / Proto-oncogene c-Ret


Mass: 68651.352 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RET, CDHF12, CDHR16, PTC, RET51 / Production host: Cricetulus griseus (Chinese hamster)
References: UniProt: P07949, receptor protein-tyrosine kinase

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Neurturin-GFRa2-RET extracellular complexCOMPLEX#1-#30MULTIPLE SOURCES
2NeurturinCOMPLEX#11RECOMBINANT
3GDNF family receptor alpha-2GFRαCOMPLEX#21RECOMBINANT
4Proto-oncogene tyrosine-protein kinase receptor RetCOMPLEX#31RECOMBINANT
Molecular weightValue: 0.254 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
34Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Cricetulus griseus (Chinese hamster)10029
34Cricetulus griseus (Chinese hamster)10029
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 38 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM software
IDNameCategory
7UCSF Chimeramodel fitting
8Cootmodel fitting
10PHENIXmodel refinement
11RosettaEMmodel refinement
12Cootmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 6.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 186903 / Symmetry type: POINT
Atomic model buildingB value: 220 / Protocol: FLEXIBLE FIT / Space: REAL

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