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- EMDB-41885: Structure of the HER2/HER4/BTC Heterodimer Extracellular Domain -

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Basic information

Entry
Database: EMDB / ID: EMD-41885
TitleStructure of the HER2/HER4/BTC Heterodimer Extracellular Domain
Map data
Sample
  • Complex: Ternary complex of HER2/HER4/BTC
    • Protein or peptide: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Betacellulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsReceptor Tyrosine Kinase / MEMBRANE PROTEIN / TRANSFERASE
Function / homology
Function and homology information


establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / epidermal growth factor receptor activity / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / Inhibition of Signaling by Overexpressed EGFR / neuregulin receptor activity / EGFR interacts with phospholipase C-gamma / cardiac muscle tissue regeneration ...establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / epidermal growth factor receptor activity / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / Inhibition of Signaling by Overexpressed EGFR / neuregulin receptor activity / EGFR interacts with phospholipase C-gamma / cardiac muscle tissue regeneration / negative regulation of immature T cell proliferation in thymus / ERBB3:ERBB2 complex / PLCG1 events in ERBB2 signaling / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / immature T cell proliferation in thymus / RNA polymerase I core binding / mitochondrial fragmentation involved in apoptotic process / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / semaphorin receptor complex / GABA receptor binding / Signaling by EGFR / transmembrane receptor protein tyrosine kinase activator activity / positive regulation of urine volume / PI3K events in ERBB4 signaling / negative regulation of epithelial cell apoptotic process / mammary gland epithelial cell differentiation / embryonic pattern specification / Signaling by ERBB4 / regulation of microtubule-based process / positive regulation of protein localization to cell surface / ErbB-3 class receptor binding / ERBB2 Regulates Cell Motility / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / PI3K events in ERBB2 signaling / neural crest cell migration / epithelial cell apoptotic process / neurotransmitter receptor localization to postsynaptic specialization membrane / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of Rho protein signal transduction / epidermal growth factor receptor binding / neuromuscular junction development / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / cell fate commitment / GAB1 signalosome / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / positive regulation of transcription by RNA polymerase I / oligodendrocyte differentiation / cell surface receptor signaling pathway via JAK-STAT / Long-term potentiation / semaphorin-plexin signaling pathway / positive regulation of cell division / cellular response to epidermal growth factor stimulus / Signaling by ERBB2 / positive regulation of cell adhesion / SHC1 events in ERBB4 signaling / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of protein targeting to membrane / GABA-ergic synapse / mammary gland alveolus development / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / regulation of angiogenesis / neurogenesis / SHC1 events in ERBB2 signaling / coreceptor activity / regulation of ERK1 and ERK2 cascade / Schwann cell development / basal plasma membrane / Nuclear signaling by ERBB4 / positive regulation of epithelial cell proliferation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of cardiac muscle cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / synapse assembly / Downregulation of ERBB4 signaling / myelination / lactation / regulation of cell migration / phosphatidylinositol 3-kinase/protein kinase B signal transduction / Downregulation of ERBB2:ERBB3 signaling / Constitutive Signaling by Overexpressed ERBB2 / positive regulation of mitotic nuclear division / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / positive regulation of MAP kinase activity
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 / Growth factor receptor cysteine-rich domain superfamily / : / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain signature 1. / 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
Receptor tyrosine-protein kinase erbB-2 / Probetacellulin / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.27 Å
AuthorsTrenker R / Diwanji D / Bingham T / Verba KA / Jura N
Funding support Germany, United States, 3 items
OrganizationGrant numberCountry
German Research Foundation (DFG)TR 1668/1-1 Germany
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM139636 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA274502 United States
CitationJournal: To Be Published
Title: Structure of the HER2/HER4/BTC Heterodimer Extracellular Domain
Authors: Trenker R / Diwanji D / Bingham T / Verba KA / Jura N
History
DepositionSep 10, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateMar 13, 2024-
Current statusMar 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41885.png

Downloads & links

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Map

FileDownload / File: emd_41885.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.835 Å
Density
Contour LevelBy AUTHOR: 0.0694
Minimum - Maximum-0.40169397 - 0.7745753
Average (Standard dev.)-0.000090608 (±0.02161514)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 320.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_41885_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41885_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_41885_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of HER2/HER4/BTC

EntireName: Ternary complex of HER2/HER4/BTC
Components
  • Complex: Ternary complex of HER2/HER4/BTC
    • Protein or peptide: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-2
    • Protein or peptide: Betacellulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of HER2/HER4/BTC

SupramoleculeName: Ternary complex of HER2/HER4/BTC / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: HER2 and HER4 Receptors were expressed in EXPI293F cells. The ligand BTC was expressed in E. coli Origami B (DE3)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 284.435 KDa

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Macromolecule #1: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4

MacromoleculeName: Isoform JM-A CYT-1 of Receptor tyrosine-protein kinase erbB-4
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.909648 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSVCAGTENK LSSLSDLEQQ YRALRKYYEN CEVVMGNLEI TSIEHNRDLS FLRSVREVTG YVLVALNQFR YLPLENLRII RGTKLYEDR YALAIFLNYR KDGNFGLQEL GLKNLTEILN GGVYVDQNKF LCYADTIHWQ DIVRNPWPSN LTLVSTNGSS G CGRCHKSC ...String:
QSVCAGTENK LSSLSDLEQQ YRALRKYYEN CEVVMGNLEI TSIEHNRDLS FLRSVREVTG YVLVALNQFR YLPLENLRII RGTKLYEDR YALAIFLNYR KDGNFGLQEL GLKNLTEILN GGVYVDQNKF LCYADTIHWQ DIVRNPWPSN LTLVSTNGSS G CGRCHKSC TGRCWGPTEN HCQTLTRTVC AEQCDGRCYG PYVSDCCHRE CAGGCSGPKD TDCFACMNFN DSGACVTQCP QT FVYNPTT FQLEHNFNAK YTYGAFCVKK CPHNFVVDSS SCVRACPSSK MEVEENGIKM CKPCTDICPK ACDGIGTGSL MSA QTVDSS NIDKFINCTK INGNLIFLVT GIHGDPYNAI EAIDPEKLNV FRTVREITGF LNIQSWPPNM TDFSVFSNLV TIGG RVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG MVCNH LCSS DGCWGPGPDQ CLSCRRFSRG RICIESCNLY DGEFREFENG SICVECDPQC EKMEDGLLTC HGPGPDNCTK CSHFKD GPN CVEKCPDGLQ GANSFIFKYA DPDRECHPCH PNCTQGCNGP TSHDCI

UniProtKB: Receptor tyrosine-protein kinase erbB-4

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Macromolecule #2: Receptor tyrosine-protein kinase erbB-2

MacromoleculeName: Receptor tyrosine-protein kinase erbB-2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.888008 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVCTGTDMKL RLPASPETHL DMLRHLYQGC QVVQGNLELT YLPTNASLSF LQDIQEVQGY VLIAHNQVRQ VPLQRLRIVR GTQLFEDNY ALAVLDNGDP LNNTTPVTGA SPGGLRELQL RSLTEILKGG VLIQRNPQLC YQDTILWKDI FHKNNQLALT L IDTNRSRA ...String:
QVCTGTDMKL RLPASPETHL DMLRHLYQGC QVVQGNLELT YLPTNASLSF LQDIQEVQGY VLIAHNQVRQ VPLQRLRIVR GTQLFEDNY ALAVLDNGDP LNNTTPVTGA SPGGLRELQL RSLTEILKGG VLIQRNPQLC YQDTILWKDI FHKNNQLALT L IDTNRSRA CHPCSPMCKG SRCWGESSED CQSLTRTVCA GGCARCKGPL PTDCCHEQCA AGCTGPKHSD CLACLHFNHS GI CELHCPA LVTYNTDTFE SMPNPEGRYT FGASCVTACP YNYLSTDVGS CTLVCPLHNQ EVTAEDGTQR CEKCSKPCAR VCY GLGMEH LREVRAVTSA NIQEFAGCKK IFGSLAFLPE SFDGDPASNT APLQPEQLQV FETLEEITGY LYISAWPDSL PDLS VFQNL QVIRGRILHN GAYSLTLQGL GISWLGLRSL RELGSGLALI HHNTHLCFVH TVPWDQLFRN PHQALLHTAN RPEDE CVGE GLACHQLCAR GHCWGPGPTQ CVNCSQFLRG QECVEECRVL QGLPREYVNA RHCLPCHPEC QPQNGSVTCF GPEADQ CVA CAHYKDPPFC VARCPSGVKP DLSYMPIWKF PDEEGACQPC PIN

UniProtKB: Receptor tyrosine-protein kinase erbB-2

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Macromolecule #3: Betacellulin

MacromoleculeName: Betacellulin / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.630513 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
GHFSRCPKQY KHYCIKGRCR FVVAEQTPSC VCDEGYIGAR CERVDLFY

UniProtKB: Probetacellulin

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Macromolecule #9: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 9 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

BufferpH: 7.4
Component:
ConcentrationNameFormula
50.0 mMTris
150.0 mMsodium chlorideNaCl
0.5 mMDDM
GridModel: Quantifoil R1.2/1.3 / Support film - Material: GRAPHENE OXIDE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 293 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Average electron dose: 45.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7mn5


Details: Model assembled using 7MN5, 3U7U, and AF-P35070-F1.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.27 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 148541
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.15)
FSC plot (resolution estimation)

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