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- EMDB-25522: Cryo-EM structure of the extracellular module of the full-length ... -

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Basic information

Entry
Database: EMDB / ID: EMD-25522
TitleCryo-EM structure of the extracellular module of the full-length EGFR bound to EGF "tips-juxtaposed" conformation
Map dataWT:EGF_jux
Sample
  • Complex: full-length human EGFR:EGF complex
    • Protein or peptide: Epidermal growth factor receptor
    • Protein or peptide: Epidermal growth factor
Keywordsreceptor tyrosine kinases / epidermal growth factor receptor / SIGNALING PROTEIN
Function / homology
Function and homology information


positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of epithelial tube formation / positive regulation of cerebellar granule cell precursor proliferation / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / cerebellar granule cell precursor proliferation / regulation of calcium ion import / transmembrane receptor protein tyrosine kinase activator activity ...positive regulation of hyaluronan biosynthetic process / negative regulation of secretion / negative regulation of cholesterol efflux / positive regulation of epithelial tube formation / positive regulation of cerebellar granule cell precursor proliferation / positive regulation of protein localization to early endosome / regulation of protein localization to cell surface / cerebellar granule cell precursor proliferation / regulation of calcium ion import / transmembrane receptor protein tyrosine kinase activator activity / Developmental Lineage of Pancreatic Acinar Cells / positive regulation of ubiquitin-dependent protein catabolic process / Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin / multivesicular body, internal vesicle lumen / negative regulation of cardiocyte differentiation / Shc-EGFR complex / epidermal growth factor receptor binding / positive regulation of protein kinase C signaling / positive regulation of peptidyl-threonine phosphorylation / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / regulation of receptor signaling pathway via JAK-STAT / regulation of peptidyl-tyrosine phosphorylation / positive regulation of DNA binding / epidermal growth factor binding / NFE2L2 regulating tumorigenic genes / response to UV-A / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / morphogenesis of an epithelial fold / PTK6 promotes HIF1A stabilization / ERBB2 Activates PTK6 Signaling / digestive tract morphogenesis / branching morphogenesis of an epithelial tube / Signaling by EGFR / 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 / Respiratory syncytial virus (RSV) attachment and entry / positive regulation of receptor internalization / Signaling by ERBB4 / PI3K events in ERBB2 signaling / positive regulation of phosphorylation / positive regulation of peptidyl-serine phosphorylation / mammary gland alveolus development / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / hair follicle development / MAP kinase kinase kinase activity / GAB1 signalosome / positive regulation of G1/S transition of mitotic cell cycle / embryonic placenta development / salivary gland morphogenesis / ERK1 and ERK2 cascade / positive regulation of endothelial cell proliferation / Signaling by ERBB2 / GRB2 events in EGFR signaling / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / SHC1 events in EGFR signaling / transmembrane receptor protein tyrosine kinase activity / EGFR Transactivation by Gastrin / positive regulation of endothelial cell migration / GRB2 events in ERBB2 signaling / positive regulation of mitotic nuclear division / SHC1 events in ERBB2 signaling / ossification / NOTCH3 Activation and Transmission of Signal to the Nucleus / positive regulation of DNA repair / basal plasma membrane / cellular response to epidermal growth factor stimulus / guanyl-nucleotide exchange factor activity / platelet alpha granule lumen / EGFR downregulation / positive regulation of DNA replication / epithelial cell proliferation / Signal transduction by L1 / positive regulation of epithelial cell proliferation / positive regulation of protein localization to plasma membrane / cellular response to amino acid stimulus / growth factor activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to estradiol stimulus / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / cell-cell adhesion / receptor protein-tyrosine kinase / negative regulation of protein catabolic process / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of miRNA transcription / kinase binding / ruffle membrane / positive regulation of protein phosphorylation / epidermal growth factor receptor signaling pathway
Similarity search - Function
Pro-epidermal growth factor / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Calcium-binding EGF domain / : / Epidermal growth factor receptor transmembrane-juxtamembrane segment ...Pro-epidermal growth factor / : / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / : / Calcium-binding EGF 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 / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / EGF-like domain / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / EGF-type aspartate/asparagine hydroxylation site / Furin-like repeat / Furin-like repeats / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / 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 / Pro-epidermal growth factor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsHuang Y / Ognjenovic J
Funding support United States, 2 items
OrganizationGrant numberCountry
Canada Excellence Research Chair Award United States
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 24, 2021-
Header (metadata) releaseDec 22, 2021-
Map releaseDec 22, 2021-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7syd
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25522.png

Downloads & links

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Map

FileDownload / File: emd_25522.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationWT:EGF_jux
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 323.82 Å		1.08 Å/pix.
x 300 pix.
= 323.82 Å		1.08 Å/pix.
x 300 pix.
= 323.82 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0794 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2 / Movie #1: 0.3
Minimum - Maximum-0.54196143 - 1.4651874
Average (Standard dev.)-0.000043390337 (±0.038118795)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 323.81998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.07941.07941.0794
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z323.820323.820323.820
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.5421.465-0.000

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Supplemental data

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Sample components

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Entire : full-length human EGFR:EGF complex

EntireName: full-length human EGFR:EGF complex
Components
  • Complex: full-length human EGFR:EGF complex
    • Protein or peptide: Epidermal growth factor receptor
    • Protein or peptide: Epidermal growth factor

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Supramolecule #1: full-length human EGFR:EGF complex

SupramoleculeName: full-length human EGFR:EGF complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Epidermal growth factor receptor

MacromoleculeName: Epidermal growth factor receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 134.433328 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV ...String:
MRPSGTAGAA LLALLAALCP ASRALEEKKV CQGTSNKLTQ LGTFEDHFLS LQRMFNNCEV VLGNLEITYV QRNYDLSFLK TIQEVAGYV LIALNTVERI PLENLQIIRG NMYYENSYAL AVLSNYDANK TGLKELPMRN LQEILHGAVR FSNNPALCNV E SIQWRDIV SSDFLSNMSM DFQNHLGSCQ KCDPSCPNGS CWGAGEENCQ KLTKIICAQQ CSGRCRGKSP SDCCHNQCAA GC TGPRESD CLVCRKFRNE ATCKDTCPPL MLYNPTTYQM DVNPEGKYSF GATCVKKCPR NYVVTDHGSC VRACGADSYE MEE DGVRKC KKCEGPCRKV CNGIGIGEFK DSLSINATNI KHFKNCTSIS GDLHILPVAF RGDSFTHTPP LDPQELDILK TVKE ITGFL LIQAWPENRT DLHAFENLEI IRGRTKQHGQ FSLAVVSLNI TSLGLRSLKE ISDGDVIISG NKNLCYANTI NWKKL FGTS GQKTKIISNR GENSCKATGQ VCHALCSPEG CWGPEPRDCV SCRNVSRGRE CVDKCNLLEG EPREFVENSE CIQCHP ECL PQAMNITCTG RGPDNCIQCA HYIDGPHCVK TCPAGVMGEN NTLVWKYADA GHVCHLCHPN CTYGCTGPGL EGCPTNG PK IPSIATGMVG ALLLLLVVAL GIGLFMRRRH IVRKRTLRRL LQERELVEPL TPSGEAPNQA LLRILKETEF KKIKVLGS G AFGTVYKGLW IPEGEKVKIP VAIKELREAT SPKANKEILD EAYVMASVDN PHVCRLLGIC LTSTVQLITQ LMPFGCLLD YVREHKDNIG SQYLLNWCVQ IAKGMNYLED RRLVHRDLAA RNVLVKTPQH VKITDFGLAK LLGAEEKEYH AEGGKVPIKW MALESILHR IYTHQSDVWS YGVTVWELMT FGSKPYDGIP ASEISSILEK GERLPQPPIC TIDVYMIMVK CWMIDADSRP K FRELIIEF SKMARDPQRY LVIQGDERMH LPSPTDSNFY RALMDEEDMD DVVDADEYLI PQQGFFSSPS TSRTPLLSSL SA TSNNSTV ACIDRNGLQS CPIKEDSFLQ RYSSDPTGAL TEDSIDDTFL PVPEYINQSV PKRPAGSVQN PVYHNQPLNP APS RDPHYQ DPHSTAVGNP EYLNTVQPTC VNSTFDSPAH WAQKGSHQIS LDNPDYQQDF FPKEAKPNGI FKGSTAENAE YLRV APQSS EFIGA

UniProtKB: Epidermal growth factor receptor

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Macromolecule #2: Epidermal growth factor

MacromoleculeName: Epidermal growth factor / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.229027 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
NSDSECPLSH DGYCLHDGVC MYIEALDKYA CNCVVGYIGE RCQYRDLKWW ELR

UniProtKB: Pro-epidermal growth factor

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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

Concentration0.5 mg/mL
BufferpH: 8
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 7.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Details: ab-initio model reconstructed from experimental data
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. v2) / Number images used: 105728
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v2)
Final 3D classificationNumber classes: 10 / Avg.num./class: 100000 / Software - Name: cryoSPARC (ver. v2)

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