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- EMDB-41886: Structure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain -

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Entry
Database: EMDB / ID: EMD-41886
TitleStructure of the HER2/HER4/NRG1b Heterodimer Extracellular Domain
Map data
Sample
  • Complex: Ternary complex of HER2/HER4/NRG1b
    • 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: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsReceptor Tyrosine Kinase / MEMBRANE PROTEIN / TRANSFERASE
Function / homology
Function and homology information


ERBB3 signaling pathway / positive regulation of peptidyl-tyrosine autophosphorylation / sequestering of metal ion / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation ...ERBB3 signaling pathway / positive regulation of peptidyl-tyrosine autophosphorylation / sequestering of metal ion / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation / neuregulin receptor activity / negative regulation of secretion / cardiac muscle tissue regeneration / endocardial cell differentiation / negative regulation of immature T cell proliferation in thymus / animal organ development / ERBB3:ERBB2 complex / 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 / neural crest cell development / cardiac muscle cell myoblast differentiation / embryonic pattern specification / mammary gland development / GABA receptor binding / cell communication / semaphorin receptor complex / PI3K events in ERBB4 signaling / cardiac muscle cell differentiation / mammary gland epithelial cell differentiation / chemorepellent activity / ventricular trabecula myocardium morphogenesis / ErbB-3 class receptor binding / regulation of microtubule-based process / positive regulation of protein localization to cell surface / Sema4D induced cell migration and growth-cone collapse / motor neuron axon guidance / regulation of postsynaptic neurotransmitter receptor internalization / activation of transmembrane receptor protein tyrosine kinase activity / neural crest cell migration / epidermal growth factor receptor activity / ERBB signaling pathway / neurotransmitter receptor localization to postsynaptic specialization membrane / PLCG1 events in ERBB2 signaling / negative regulation of cardiac muscle cell apoptotic process / ERBB2-EGFR signaling pathway / epidermal growth factor receptor binding / positive regulation of Rho protein signal transduction / ERBB2 Activates PTK6 Signaling / neuromuscular junction development / positive regulation of transcription by RNA polymerase I / 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 / transmembrane receptor protein tyrosine kinase activator activity / enzyme-linked receptor protein signaling pathway / ERBB2-ERBB3 signaling pathway / protein tyrosine kinase activator activity / Signaling by ERBB4 / oligodendrocyte differentiation / ERBB2 Regulates Cell Motility / cell surface receptor signaling pathway via JAK-STAT / Long-term potentiation / semaphorin-plexin signaling pathway / PI3K events in ERBB2 signaling / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / SHC1 events in ERBB4 signaling / positive regulation of protein targeting to membrane / cell fate commitment / mammary gland alveolus development / regulation of angiogenesis / coreceptor activity / Schwann cell development / positive regulation of cardiac muscle cell proliferation / cell surface receptor protein tyrosine kinase signaling pathway / GABA-ergic synapse / Nuclear signaling by ERBB4 / positive regulation of tyrosine phosphorylation of STAT protein / Signaling by ERBB2 / synapse assembly / lactation / cellular response to epidermal growth factor stimulus / TFAP2 (AP-2) family regulates transcription of growth factors and their receptors / myelination / regulation of cell migration / activation of protein kinase B activity / Downregulation of ERBB4 signaling / GRB2 events in ERBB2 signaling / transmembrane receptor protein tyrosine kinase activity / phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of ERK1 and ERK2 cascade
Similarity search - Function
Neuregulin, C-terminal / Neuregulin-1 / Neuregulin / Neuregulin intracellular region / : / 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 ...Neuregulin, C-terminal / Neuregulin-1 / Neuregulin / Neuregulin intracellular region / : / 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 / EGF-like domain / Furin-like repeat / Furin-like repeats / Immunoglobulin I-set / Immunoglobulin I-set domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich domain superfamily / : / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Receptor tyrosine-protein kinase erbB-2 / Pro-neuregulin-1, membrane-bound isoform / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.31 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-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41886.png

Downloads & links

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Map

FileDownload / File: emd_41886.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
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0464
Minimum - Maximum-0.9736661 - 1.7285682
Average (Standard dev.)-0.000041642543 (±0.027535614)
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_41886_msk_1.map
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Half map: #2

Fileemd_41886_half_map_1.map
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Half map: #1

Fileemd_41886_half_map_2.map
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Sample components

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Entire : Ternary complex of HER2/HER4/NRG1b

EntireName: Ternary complex of HER2/HER4/NRG1b
Components
  • Complex: Ternary complex of HER2/HER4/NRG1b
    • 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: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of HER2/HER4/NRG1b

SupramoleculeName: Ternary complex of HER2/HER4/NRG1b / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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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: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform

MacromoleculeName: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 5.890792 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString:
SHLVKCAEKE KTFCVNGGEC FMVKDLSNPS RYLCKCPNEF TGDRCQNYVM AS

UniProtKB: Pro-neuregulin-1, membrane-bound isoform

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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 and 3U7U
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4) / Number images used: 289192
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4)
FSC plot (resolution estimation)

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