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- PDB-4ux8: RET recognition of GDNF-GFRalpha1 ligand by a composite binding s... -
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Basic information
Entry | Database: PDB / ID: 4ux8 | |||||||||
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Title | RET recognition of GDNF-GFRalpha1 ligand by a composite binding site promotes membrane-proximal self-association | |||||||||
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![]() | SIGNALING PROTEIN / VERTEBRATE DEVELOPMENT / HUMAN DISEASES / PART OF THE RET-GFL- GFRA COMPLEX | |||||||||
Function / homology | ![]() chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity ...chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis / ureteric bud formation / positive regulation of ureteric bud formation / regulation of semaphorin-plexin signaling pathway / postganglionic parasympathetic fiber development / positive regulation of monooxygenase activity / glial cell-derived neurotrophic factor receptor activity / glial cell-derived neurotrophic factor receptor binding / RET signaling / GDF15-GFRAL signaling pathway / Peyer's patch morphogenesis / positive regulation of metanephric glomerulus development / posterior midgut development / ureter maturation / embryonic epithelial tube formation / glial cell-derived neurotrophic factor receptor signaling pathway / lymphocyte migration into lymphoid organs / : / regulation of morphogenesis of a branching structure / membrane protein proteolysis / neurotrophin receptor activity / positive regulation of peptidyl-serine phosphorylation of STAT protein / regulation of dopamine uptake involved in synaptic transmission / Formation of the ureteric bud / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / peristalsis / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of dopamine secretion / sympathetic nervous system development / peripheral nervous system development / innervation / organ induction / plasma membrane protein complex / regulation of stem cell differentiation / commissural neuron axon guidance / neuron maturation / metanephros development / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / NCAM1 interactions / mRNA stabilization / positive regulation of cell adhesion mediated by integrin / RAF/MAP kinase cascade / neural crest cell migration / ureteric bud development / branching involved in ureteric bud morphogenesis / regulation of axonogenesis / response to pain / 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 / transmembrane receptor protein tyrosine kinase activity / regulation of cell adhesion / embryonic organ development / cellular response to retinoic acid / NPAS4 regulates expression of target genes / multivesicular body / adult locomotory behavior / kidney development / axon guidance / receptor protein-tyrosine kinase / positive regulation of cell differentiation / growth factor activity / neuron differentiation / receptor tyrosine kinase binding / activation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of neuron projection development / integrin binding / male gonad development / positive regulation of peptidyl-tyrosine phosphorylation / MAPK cascade / neuron projection development / cell migration / retina development in camera-type eye / regulation of gene expression / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / receptor complex / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / endosome membrane / early endosome / positive regulation of cell migration / response to xenobiotic stimulus / protein phosphorylation / external side of plasma membrane / axon / signaling receptor binding / neuronal cell body / positive regulation of cell population proliferation Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 24 Å | |||||||||
![]() | Goodman, K. / Kjaer, S. / Beuron, F. / Knowles, P. / Nawrotek, A. / Burns, E. / Purkiss, A. / George, R. / Santoro, M. / Morris, E.P. / McDonald, N.Q. | |||||||||
![]() | ![]() Title: RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Authors: Kerry M Goodman / Svend Kjær / Fabienne Beuron / Phillip P Knowles / Agata Nawrotek / Emily M Burns / Andrew G Purkiss / Roger George / Massimo Santoro / Edward P Morris / Neil Q McDonald / ![]() ![]() Abstract: The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a ...The RET receptor tyrosine kinase is essential to vertebrate development and implicated in multiple human diseases. RET binds a cell surface bipartite ligand comprising a GDNF family ligand and a GFRα coreceptor, resulting in RET transmembrane signaling. We present a hybrid structural model, derived from electron microscopy (EM) and low-angle X-ray scattering (SAXS) data, of the RET extracellular domain (RET(ECD)), GDNF, and GFRα1 ternary complex, defining the basis for ligand recognition. RET(ECD) envelopes the dimeric ligand complex through a composite binding site comprising four discrete contact sites. The GFRα1-mediated contacts are crucial, particularly close to the invariant RET calcium-binding site, whereas few direct contacts are made by GDNF, explaining how distinct ligand/coreceptor pairs are accommodated. The RET(ECD) cysteine-rich domain (CRD) contacts both ligand components and makes homotypic membrane-proximal interactions occluding three different antibody epitopes. Coupling of these CRD-mediated interactions suggests models for ligand-induced RET activation and ligand-independent oncogenic deregulation. | |||||||||
History |
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PDBx/mmCIF format | ![]() | 334.4 KB | Display | ![]() |
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-Validation report
Summary document | ![]() | 865.5 KB | Display | ![]() |
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Full document | ![]() | 1005 KB | Display | |
Data in XML | ![]() | 65.3 KB | Display | |
Data in CIF | ![]() | 96.2 KB | Display | |
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-Related structure data
Related structure data | ![]() 2712MC ![]() 2713C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 67922.539 Da / Num. of mol.: 2 / Fragment: RET EXTRACELLULAR DOMAIN, RESIDUES 29-635 / Mutation: YES Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P07949, receptor protein-tyrosine kinase #2: Protein | Mass: 51091.277 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() #3: Protein | Mass: 15096.242 Da / Num. of mol.: 2 / Fragment: MATURE, UNP RESIDUES 78-211 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #4: Polysaccharide | Source method: isolated from a genetically manipulated source #5: Chemical | ChemComp-CA / Sequence details | RESIDUES 509 TO 635 ARE NOT IN THE MODEL | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Reconstituted mammalian RETecd-GDNF-GFRa1 ternary complex Type: COMPLEX |
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Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO |
EM staining | Type: NEGATIVE / Material: uranyl acetate |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Tecnai F20 / Image courtesy: FEI Company |
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Microscopy | Model: FEI TECNAI F20 / Date: Nov 8, 2012 |
Electron gun | Electron source: ![]() |
Electron lens | Mode: OTHER / Nominal magnification: 80000 X / Nominal defocus min: 900 nm |
Image recording | Electron dose: 100 e/Å2 / Film or detector model: TVIPS TEMCAM-F415 (4k x 4k) |
Image scans | Num. digital images: 1200 |
Radiation wavelength | Relative weight: 1 |
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Processing
EM software |
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Symmetry | Point symmetry: C2 (2 fold cyclic) | ||||||||||||
3D reconstruction | Method: ANGULAR RECONSTITUTION / Resolution: 24 Å / Num. of particles: 8519 Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-2712. (DEPOSITION ID: 12696). Symmetry type: POINT | ||||||||||||
Refinement | Highest resolution: 24 Å | ||||||||||||
Refinement step | Cycle: LAST / Highest resolution: 24 Å
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