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- EMDB-20575: Cryo-EM structure of RET/GFRa1/GDNF extracellular complex -

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Basic information

Entry
Database: EMDB / ID: EMD-20575
TitleCryo-EM structure of RET/GFRa1/GDNF extracellular complex
Map dataCryo-EM structure of RET/GFR%u03B11/GDNF extracellular complex. The 3D refinement was applied with C2 symmetry.
Sample
  • Complex: RET, GFRAL and GDF15 extracellular complex
    • Protein or peptide: Glial cell line-derived neurotrophic factor
    • Protein or peptide: GDNF family receptor alpha-1
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase receptor Ret
  • Ligand: CALCIUM ION
KeywordsRET / receptor tyrosine kinase / cryo-EM / SIGNALING PROTEIN
Function / homology
Function and homology information


chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / regulation of morphogenesis of a branching structure / 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 ...chemoattractant activity involved in axon guidance / mesenchymal to epithelial transition involved in metanephros morphogenesis / dorsal spinal cord development / postsynaptic membrane organization / regulation of morphogenesis of a branching structure / 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 / 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 / neurotrophin receptor activity / positive regulation of peptidyl-serine phosphorylation of STAT protein / membrane protein proteolysis / Formation of the ureteric bud / regulation of dopamine uptake involved in synaptic transmission / positive regulation of neuron maturation / neuron cell-cell adhesion / Formation of the nephric duct / enteric nervous system development / peristalsis / positive regulation of dopamine secretion / positive regulation of branching involved in ureteric bud morphogenesis / peripheral nervous system development / sympathetic nervous system development / innervation / organ induction / plasma membrane protein complex / regulation of stem cell differentiation / commissural neuron axon guidance / neuron maturation / positive regulation of extrinsic apoptotic signaling pathway in absence of ligand / metanephros development / NCAM1 interactions / mRNA stabilization / positive regulation of cell adhesion mediated by integrin / ureteric bud development / neural crest cell migration / extrinsic component of membrane / branching involved in ureteric bud morphogenesis / regulation of axonogenesis / response to pain / homophilic cell adhesion via plasma membrane adhesion molecules / RET signaling / positive regulation of cell size / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / embryonic organ development / regulation of cell adhesion / cellular response to retinoic acid / NPAS4 regulates expression of target genes / transmembrane receptor protein tyrosine kinase activity / multivesicular body / adult locomotory behavior / kidney development / axon guidance / positive regulation of cell differentiation / growth factor activity / receptor protein-tyrosine kinase / : / receptor tyrosine kinase binding / positive regulation of neuron projection development / male gonad development / positive regulation of peptidyl-tyrosine phosphorylation / MAPK cascade / neuron projection development / integrin binding / cell migration / retina development in camera-type eye / signaling receptor activity / nervous system development / RAF/MAP kinase cascade / regulation of gene expression / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / early endosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / cell surface receptor signaling pathway / 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 / positive regulation of cell population proliferation / calcium ion binding
Similarity search - Function
Glial cell line-derived neurotrophic factor receptor, alpha 1 / Glial cell line-derived neurotrophic factor / : / 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 ...Glial cell line-derived neurotrophic factor receptor, alpha 1 / Glial cell line-derived neurotrophic factor / : / 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 (TGF-beta) family / 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
Proto-oncogene tyrosine-protein kinase receptor Ret / Glial cell line-derived neurotrophic factor / GDNF family receptor alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsLi J / Shang GJ
CitationJournal: Elife / Year: 2019
Title: Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands.
Authors: Jie Li / Guijun Shang / Yu-Ju Chen / Chad A Brautigam / Jen Liou / Xuewu Zhang / Xiao-Chen Bai /
Abstract: RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ...RET is a receptor tyrosine kinase (RTK) that plays essential roles in development and has been implicated in several human diseases. Different from most of RTKs, RET requires not only its cognate ligands but also co-receptors for activation, the mechanisms of which remain unclear due to lack of high-resolution structures of the ligand/co-receptor/receptor complexes. Here, we report cryo-EM structures of the extracellular region ternary complexes of GDF15/GFRAL/RET, GDNF/GFRα1/RET, NRTN/GFRα2/RET and ARTN/GFRα3/RET. These structures reveal that all the four ligand/co-receptor pairs, while using different atomic interactions, induce a specific dimerization mode of RET that is poised to bring the two kinase domains into close proximity for cross-phosphorylation. The NRTN/GFRα2/RET dimeric complex further pack into a tetrameric assembly, which is shown by our cell-based assays to regulate the endocytosis of RET. Our analyses therefore reveal both the common mechanism and diversification in the activation of RET by different ligands.
History
DepositionAug 8, 2019-
Header (metadata) releaseOct 2, 2019-
Map releaseOct 2, 2019-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.03
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  • Surface view with fitted model
  • Atomic models: PDB-6q2n
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20575.png

Downloads & links

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Map

FileDownload / File: emd_20575.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of RET/GFR%u03B11/GDNF extracellular complex. The 3D refinement was applied with C2 symmetry.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 220 pix.
= 235.4 Å		1.07 Å/pix.
x 220 pix.
= 235.4 Å		1.07 Å/pix.
x 220 pix.
= 235.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.07 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.09675588 - 0.15205897
Average (Standard dev.)0.00042984853 (±0.007031841)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 235.40001 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.071.071.07
M x/y/z220220220
origin x/y/z0.0000.0000.000
length x/y/z235.400235.400235.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ320320320
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS220220220
D min/max/mean-0.0970.1520.000

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Supplemental data

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Sample components

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Entire : RET, GFRAL and GDF15 extracellular complex

EntireName: RET, GFRAL and GDF15 extracellular complex
Components
  • Complex: RET, GFRAL and GDF15 extracellular complex
    • Protein or peptide: Glial cell line-derived neurotrophic factor
    • Protein or peptide: GDNF family receptor alpha-1
    • Protein or peptide: Proto-oncogene tyrosine-protein kinase receptor Ret
  • Ligand: CALCIUM ION

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Supramolecule #1: RET, GFRAL and GDF15 extracellular complex

SupramoleculeName: RET, GFRAL and GDF15 extracellular complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 200 kDa/nm

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Macromolecule #1: Glial cell line-derived neurotrophic factor

MacromoleculeName: Glial cell line-derived neurotrophic factor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.096242 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
SPDKQMAVLP RRERNRQAAA ANPENSRGKG RRGQRGKNRG CVLTAIHLNV TDLGLGYETK EELIFRYCSG SCDAAETTYD KILKNLSRN RRLVSDKVGQ ACCRPIAFDD DLSFLDDNLV YHILRKHSAK RCGCI

UniProtKB: Glial cell line-derived neurotrophic factor

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Macromolecule #2: GDNF family receptor alpha-1

MacromoleculeName: GDNF family receptor alpha-1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.358551 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DRLDCVKASD QCLKEQSCST KYRTLRQCVA GKETNFSLAS GLEAKDECRS AMEALKQKSL YNCRCKRGMK KEKNCLRIYW SMYQSLQGN DLLEDSPYEP VNSRLSDIFR VVPFISDVFQ QVEHIPKGNN CLDAAKACNL DDICKKYRSA YITPCTTSVS N DVCNRRKC ...String:
DRLDCVKASD QCLKEQSCST KYRTLRQCVA GKETNFSLAS GLEAKDECRS AMEALKQKSL YNCRCKRGMK KEKNCLRIYW SMYQSLQGN DLLEDSPYEP VNSRLSDIFR VVPFISDVFQ QVEHIPKGNN CLDAAKACNL DDICKKYRSA YITPCTTSVS N DVCNRRKC HKALRQFFDK VPAKHSYGML FCSCRDIACT ERRRQTIVPV CSYEEREKPN CLNLQDSCKT NYICRSRLAD FF TNCQPES RSVSSCLKEN YADCLLAYSG LIGTVMTPNY IDSSSLSVAP WCDCSNSGND LEECLKFLNF FKDNTCLKNA IQA FGNGSD VTVWQPAFPV QTTTATTTTA LRVKNKPLGP AGSENEIPTH VLPPCANLQA QKLKSNVSGN THLCISNGNY EKEG LGGTH HHHHHHH

UniProtKB: GDNF family receptor alpha-1

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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: 69.100812 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LYFSRDAYWE KLYVDQAAGT PLLYVHALRD APEEVPSFRL GQHLYGTYRT RLHENNWICI QEDTGLLYLN RSLDHSSWEK LSVRNHGFP LLTVYLKVFL SPTSLREGEC QWPGCARVYF SFFNTSFPAC SSLKPRELCF PETRPSFRIR ENRPPGTFHQ F RLLPVQFL ...String:
LYFSRDAYWE KLYVDQAAGT PLLYVHALRD APEEVPSFRL GQHLYGTYRT RLHENNWICI QEDTGLLYLN RSLDHSSWEK LSVRNHGFP 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 ELCRGTHHHH HHHH

UniProtKB: Proto-oncogene tyrosine-protein kinase receptor Ret

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Macromolecule #4: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

Concentration1 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Frames/image: 1-30 / Number grids imaged: 1 / Average exposure time: 15.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 46729 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: The initial model was generated in RELION.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 37098
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT / Overall B value: 190
Output model

PDB-6q2n:
Cryo-EM structure of RET/GFRa1/GDNF extracellular complex

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