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- PDB-7sz5: Cryo-EM structure of the extracellular module of the full-length ... -

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Basic information

Entry
Database: PDB / ID: 7sz5
TitleCryo-EM structure of the extracellular module of the full-length EGFR bound to TGF-alpha "tips-separated" conformation
Components
  • Epidermal growth factor receptor
  • Transforming growth factor alpha
KeywordsSIGNALING PROTEIN / receptor tyrosine kinases / epidermal growth factor receptor
Function / homology
Function and homology information


hepatocyte proliferation / transmembrane receptor protein tyrosine kinase activator activity / Cargo concentration in the ER / COPII-mediated vesicle transport / epidermal growth factor receptor binding / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR ...hepatocyte proliferation / transmembrane receptor protein tyrosine kinase activator activity / Cargo concentration in the ER / COPII-mediated vesicle transport / epidermal growth factor receptor binding / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / positive regulation of protein kinase C signaling / Inhibition of Signaling by Overexpressed EGFR / epidermal growth factor receptor activity / EGFR interacts with phospholipase C-gamma / regulation of peptidyl-tyrosine phosphorylation / epidermal growth factor binding / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / Signaling by EGFR / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / intracellular vesicle / eyelid development in camera-type eye / negative regulation of epidermal growth factor receptor signaling pathway / cerebral cortex cell migration / protein insertion into membrane / ERBB2 Regulates Cell Motility / protein tyrosine kinase activator activity / positive regulation of cell division / Respiratory syncytial virus (RSV) attachment and entry / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / mammary gland alveolus development / positive regulation of peptidyl-serine phosphorylation / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / positive regulation of G1/S transition of mitotic cell cycle / GAB1 signalosome / embryonic placenta development / salivary gland morphogenesis / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / SHC1 events in EGFR signaling / endoplasmic reticulum-Golgi intermediate compartment membrane / EGFR Transactivation by Gastrin / positive regulation of mitotic nuclear division / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / ossification / basal plasma membrane / cellular response to epidermal growth factor stimulus / positive regulation of DNA repair / positive regulation of DNA replication / epithelial cell proliferation / positive regulation of epithelial cell proliferation / Signal transduction by L1 / positive regulation of protein localization to plasma membrane / growth factor activity / cellular response to amino acid stimulus / phosphatidylinositol 3-kinase/protein kinase B signal transduction / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / ER to Golgi transport vesicle membrane / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / cell-cell adhesion / Constitutive Signaling by EGFRvIII / receptor protein-tyrosine kinase / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / negative regulation of protein catabolic process / positive regulation of miRNA transcription / epidermal growth factor receptor signaling pathway / kinase binding / ruffle membrane / Downregulation of ERBB2 signaling / positive regulation of fibroblast proliferation / cell morphogenesis / neuron differentiation / positive regulation of protein phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / HCMV Early Events / actin filament binding / cell junction / transmembrane signaling receptor activity / positive regulation of canonical Wnt signaling pathway / PIP3 activates AKT signaling / Cargo recognition for clathrin-mediated endocytosis / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / Clathrin-mediated endocytosis / ATPase binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / virus receptor activity / RAF/MAP kinase cascade
Similarity search - Function
: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain ...: / Epidermal growth factor receptor transmembrane-juxtamembrane segment / Tyrosine protein kinase, EGF/ERB/XmrK receptor / Growth factor receptor domain 4 / Growth factor receptor domain IV / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / : / EGF-like domain / 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
Epidermal growth factor receptor / Protransforming growth factor alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsHuang, Y. / Ognjenovic, J. / Karandur, D. / Miller, K. / Merk, A. / Subramaniam, S. / Kuriyan, J.
Funding support Canada, United States, 2items
OrganizationGrant numberCountry
Canada Excellence Research Chair Award Canada
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Elife / Year: 2021
Title: A molecular mechanism for the generation of ligand-dependent differential outputs by the epidermal growth factor receptor.
Authors: Yongjian Huang / Jana Ognjenovic / Deepti Karandur / Kate Miller / Alan Merk / Sriram Subramaniam / John Kuriyan /
Abstract: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation ...The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that couples the binding of extracellular ligands, such as EGF and transforming growth factor-α (TGF-α), to the initiation of intracellular signaling pathways. EGFR binds to EGF and TGF-α with similar affinity, but generates different signals from these ligands. To address the mechanistic basis of this phenomenon, we have carried out cryo-EM analyses of human EGFR bound to EGF and TGF-α. We show that the extracellular module adopts an ensemble of dimeric conformations when bound to either EGF or TGF-α. The two extreme states of this ensemble represent distinct ligand-bound quaternary structures in which the membrane-proximal tips of the extracellular module are either juxtaposed or separated. EGF and TGF-α differ in their ability to maintain the conformation with the membrane-proximal tips of the extracellular module separated, and this conformation is stabilized preferentially by an oncogenic EGFR mutation. Close proximity of the transmembrane helices at the junction with the extracellular module has been associated previously with increased EGFR activity. Our results show how EGFR can couple the binding of different ligands to differential modulation of this proximity, thereby suggesting a molecular mechanism for the generation of ligand-sensitive differential outputs in this receptor family.
History
DepositionNov 25, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 22, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: Author supporting evidence / Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_audit_support / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_audit_support.country

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Structure visualization

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Assembly

Deposited unit
A: Epidermal growth factor receptor
C: Transforming growth factor alpha
B: Epidermal growth factor receptor
D: Transforming growth factor alpha


Theoretical massNumber of molelcules
Total (without water)279,9874
Polymers279,9874
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Epidermal growth factor receptor / Proto-oncogene c-ErbB-1 / Receptor tyrosine-protein kinase erbB-1


Mass: 134433.328 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: EGFR, ERBB, ERBB1, HER1 / Production host: Homo sapiens (human)
References: UniProt: P00533, receptor protein-tyrosine kinase
#2: Protein/peptide Transforming growth factor alpha / TGF-alpha / EGF-like TGF / ETGF / TGF type 1


Mass: 5560.246 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFA / Production host: Escherichia coli (E. coli) / References: UniProt: P01135
Has protein modificationY

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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

ComponentName: Full-length human EGFR:TGF-alpha complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: UltrAuFoil R1.2/1.3
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 FIELD
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
10cryoSPARCv2initial Euler assignment
11cryoSPARCv2final Euler assignment
12cryoSPARCv2classification
13cryoSPARCv23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102206 / Symmetry type: POINT

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