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- PDB-8u4i: Structure of the HER4/NRG1b Homodimer Extracellular Domain -

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Basic information

Entry
Database: PDB / ID: 8u4i
TitleStructure of the HER4/NRG1b Homodimer Extracellular Domain
Components
  • Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
  • Receptor tyrosine-protein kinase erbB-4
KeywordsMEMBRANE PROTEIN / TRANSFERASE / Receptor Tyrosine Kinase
Function / homology
Function and homology information


ERBB3 signaling pathway / positive regulation of peptidyl-tyrosine autophosphorylation / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / activation of transmembrane receptor protein tyrosine kinase activity / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation ...ERBB3 signaling pathway / positive regulation of peptidyl-tyrosine autophosphorylation / establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / activation of transmembrane receptor protein tyrosine kinase activity / ventricular cardiac muscle cell differentiation / positive regulation of striated muscle cell differentiation / neuregulin receptor activity / cardiac muscle tissue regeneration / negative regulation of secretion / endocardial cell differentiation / negative regulation of neuron migration / ERBB2-ERBB4 signaling pathway / GRB7 events in ERBB2 signaling / neural crest cell development / mitochondrial fragmentation involved in apoptotic process / cardiac muscle cell myoblast differentiation / cell communication / mammary gland epithelial cell differentiation / PI3K events in ERBB4 signaling / cardiac muscle cell differentiation / peripheral nervous system development / embryonic pattern specification / transmembrane receptor protein tyrosine kinase activator activity / chemorepellent activity / GABA receptor binding / ventricular trabecula myocardium morphogenesis / ErbB-3 class receptor binding / mammary gland development / positive regulation of protein localization to cell surface / epidermal growth factor receptor binding / neural crest cell migration / ERBB signaling pathway / epidermal growth factor receptor activity / negative regulation of cardiac muscle cell apoptotic process / positive regulation of tyrosine phosphorylation of STAT protein / ERBB2 Activates PTK6 Signaling / neurotransmitter receptor localization to postsynaptic specialization membrane / regulation of postsynaptic neurotransmitter receptor internalization / ERBB2-ERBB3 signaling pathway / ERBB2 Regulates Cell Motility / nickel cation binding / protein tyrosine kinase activator activity / Signaling by ERBB4 / PI3K events in ERBB2 signaling / Long-term potentiation / mammary gland alveolus development / activation of protein kinase B activity / SHC1 events in ERBB4 signaling / cell fate commitment / cell surface receptor signaling pathway via JAK-STAT / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / Nuclear signaling by ERBB4 / positive regulation of cardiac muscle cell proliferation / synapse assembly / lactation / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / positive regulation of cell adhesion / GRB2 events in ERBB2 signaling / SHC1 events in ERBB2 signaling / Downregulation of ERBB4 signaling / cell surface receptor protein tyrosine kinase signaling pathway / regulation of cell migration / basal plasma membrane / peptidyl-tyrosine phosphorylation / Downregulation of ERBB2:ERBB3 signaling / cellular response to epidermal growth factor stimulus / cytokine activity / positive regulation of epithelial cell proliferation / transcription coregulator activity / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / neuromuscular junction / wound healing / Signaling by ERBB2 TMD/JMD mutants / positive regulation of protein-containing complex assembly / receptor protein-tyrosine kinase / Signaling by ERBB2 KD Mutants / postsynaptic density membrane / brain development / receptor tyrosine kinase binding / GABA-ergic synapse / integrin binding / epidermal growth factor receptor signaling pathway / Downregulation of ERBB2 signaling / neuron differentiation / positive regulation of protein phosphorylation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / PIP3 activates AKT signaling / nervous system development / heart development / protein autophosphorylation / presynaptic membrane / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / RAF/MAP kinase 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 / EGF-like 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 / EGF-like domain / 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 / 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 1. / EGF-like domain signature 2. / : / 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
Pro-neuregulin-1, membrane-bound isoform / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.38 Å
AuthorsTrenker, R. / Diwanji, D. / Bingham, T. / Verba, K.A. / Jura, N.
Funding support Germany, United States, 3items
OrganizationGrant numberCountry
German Research Foundation (DFG)TR 1668/1-1 Germany
National Institutes of Health/National Cancer Institute (NIH/NCI)CA274502 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM139636 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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 13, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor tyrosine-protein kinase erbB-4
B: Receptor tyrosine-protein kinase erbB-4
C: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
D: Isoform 6 of Pro-neuregulin-1, membrane-bound isoform
hetero molecules


Theoretical massNumber of molelcules
Total (without water)158,68920
Polymers147,9274
Non-polymers10,76216
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 4 molecules ABCD

#1: Protein Receptor tyrosine-protein kinase erbB-4 / Proto-oncogene-like protein c-ErbB-4 / Tyrosine kinase-type cell surface receptor HER4 / p180erbB4


Mass: 68072.820 Da / Num. of mol.: 2 / Fragment: intracellular domain (UNP residues 26-635)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ERBB4, HER4 / Cell line (production host): EXPI393F / Production host: Homo sapiens (human)
References: UniProt: Q15303, receptor protein-tyrosine kinase
#2: Protein Isoform 6 of Pro-neuregulin-1, membrane-bound isoform / Pro-NRG1


Mass: 5890.792 Da / Num. of mol.: 2 / Fragment: EGF-like domain (UNP residues 177-236)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NRG1, GGF, HGL, HRGA, NDF, SMDF / Production host: Escherichia coli (E. coli) / Strain (production host): Origami B(DE3) / References: UniProt: Q02297

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Sugars , 5 types, 16 molecules

#3: Polysaccharide
beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#4: Polysaccharide
alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Details

Has ligand of interestN
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: HER4/NRG1b homodimer / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Plasmid: pCDNA
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
150 mMTRIS1
2150 mMsodium chlorideNaCl1
30.5 mMDDM1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 293 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 900 nm
Image recordingElectron dose: 68.7 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1

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Processing

EM software
IDNameVersionCategory
1cryoSPARC2.15particle selection
2SerialEMimage acquisition
4cryoSPARC2.15CTF correction
9cryoSPARC2.15initial Euler assignment
10cryoSPARC2.15final Euler assignment
12cryoSPARC2.153D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.38 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 205726 / Symmetry type: POINT
Atomic model buildingPDB-ID: 3U7U

3u7u


Accession code: 3U7U / Source name: PDB / Type: experimental model

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