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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


ERBB4 signaling pathway / olfactory bulb interneuron differentiation / ERBB4-ERBB4 signaling pathway / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / mammary gland epithelial cell differentiation / ERBB3:ERBB2 complex / mammary gland alveolus development / ERBB2-ERBB4 signaling pathway ...ERBB4 signaling pathway / olfactory bulb interneuron differentiation / ERBB4-ERBB4 signaling pathway / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / mammary gland epithelial cell differentiation / ERBB3:ERBB2 complex / mammary gland alveolus development / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / mitochondrial fragmentation involved in apoptotic process / RNA polymerase I core binding / semaphorin receptor complex / transmembrane receptor protein tyrosine kinase activator activity / embryonic pattern specification / Developmental Lineage of Mammary Stem Cells / PI3K events in ERBB4 signaling / neural crest cell migration / GABA receptor binding / ErbB-3 class receptor binding / Sema4D induced cell migration and growth-cone collapse / regulation of microtubule-based process / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / epidermal growth factor receptor activity / epidermal growth factor receptor binding / PLCG1 events in ERBB2 signaling / ERBB2-EGFR signaling pathway / enzyme-linked receptor protein signaling pathway / ERBB2 Activates PTK6 Signaling / positive regulation of tyrosine phosphorylation of STAT protein / Signaling by EGFR / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2-ERBB3 signaling pathway / 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 / positive regulation of MAP kinase activity / positive regulation of Rho protein signal transduction / positive regulation of transcription by RNA polymerase I / ERBB2 Regulates Cell Motility / Developmental Lineage of Mammary Gland Myoepithelial Cells / positive regulation of cell division / Signaling by ERBB4 / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / Developmental Lineage of Mammary Gland Luminal Epithelial Cells / Long-term potentiation / regulation of angiogenesis / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / positive regulation of protein targeting to membrane / GAB1 signalosome / SHC1 events in ERBB4 signaling / regulation of ERK1 and ERK2 cascade / positive regulation of cardiac muscle cell proliferation / Schwann cell development / Nuclear signaling by ERBB4 / lactation / cell surface receptor signaling pathway via JAK-STAT / coreceptor activity / Signaling by ERBB2 / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / positive regulation of mitotic nuclear division / transmembrane receptor protein tyrosine kinase activity / synapse assembly / peptidyl-tyrosine phosphorylation / regulation of cell migration / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / positive regulation of cell adhesion / positive regulation of epithelial cell proliferation / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / cell surface receptor protein tyrosine kinase signaling pathway / cellular response to epidermal growth factor stimulus / Constitutive Signaling by Overexpressed ERBB2 / basal plasma membrane / Downregulation of ERBB4 signaling / Downregulation of ERBB2:ERBB3 signaling / wound healing / phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of translation / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / neuromuscular junction / myelin sheath / clathrin-coated endocytic vesicle membrane / Signaling by ERBB2 TMD/JMD mutants / EGFR downregulation / receptor protein-tyrosine kinase / cell population proliferation / Signaling by ERBB2 ECD mutants
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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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: Elife / Year: 2024
Title: Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation.
Authors: Raphael Trenker / Devan Diwanji / Tanner Bingham / Kliment A Verba / Natalia Jura /
Abstract: Human Epidermal growth factor Receptor 4 (HER4 or ERBB4) carries out essential functions in the development and maintenance of the cardiovascular and nervous systems. HER4 activation is regulated by ...Human Epidermal growth factor Receptor 4 (HER4 or ERBB4) carries out essential functions in the development and maintenance of the cardiovascular and nervous systems. HER4 activation is regulated by a diverse group of extracellular ligands including the neuregulin (NRG) family and betacellulin (BTC), which promote HER4 homodimerization or heterodimerization with other HER receptors. Important cardiovascular functions of HER4 are exerted via heterodimerization with its close homolog and orphan receptor, HER2. To date structural insights into ligand-mediated HER4 activation have been limited to crystallographic studies of HER4 ectodomain homodimers in complex with NRG1β. Here, we report cryo-EM structures of near full-length HER2/HER4 heterodimers and full-length HER4 homodimers bound to NRG1β and BTC. We show that the structures of the heterodimers bound to either ligand are nearly identical and that in both cases the HER2/HER4 heterodimer interface is less dynamic than those observed in structures of HER2/EGFR and HER2/HER3 heterodimers. In contrast, structures of full-length HER4 homodimers bound to NRG1β and BTC display more large-scale dynamics mirroring states previously reported for EGFR homodimers. Our structures also reveal the presence of multiple glycan modifications within HER4 ectodomains, modeled for the first time in HER receptors, that distinctively contribute to the stabilization of HER4 homodimer interfaces over those of HER2/HER4 heterodimers.
History
DepositionSep 10, 2023-
Header (metadata) releaseMar 13, 2024-
Map releaseMar 13, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 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)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 384 pix.
= 320.64 Å		0.84 Å/pix.
x 384 pix.
= 320.64 Å		0.84 Å/pix.
x 384 pix.
= 320.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
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
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Half map: #2

Fileemd_41885_half_map_1.map
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Half map: #1

Fileemd_41885_half_map_2.map
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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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