[English] 日本語
Yorodumi
- EMDB-41884: Structure of the HER4/BTC Homodimer Extracellular Domain -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: EMDB / ID: EMD-41884
TitleStructure of the HER4/BTC Homodimer Extracellular Domain
Map data
Sample
  • Complex: HER4/BTC homodimer
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-4
    • 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 / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / negative regulation of neuron migration / ERBB2-ERBB4 signaling pathway / mitochondrial fragmentation involved in apoptotic process ...establishment of planar polarity involved in nephron morphogenesis / ERBB4 signaling pathway / ERBB4-ERBB4 signaling pathway / olfactory bulb interneuron differentiation / central nervous system morphogenesis / neuregulin receptor activity / cardiac muscle tissue regeneration / negative regulation of neuron migration / ERBB2-ERBB4 signaling pathway / mitochondrial fragmentation involved in apoptotic process / GABA receptor binding / PI3K events in ERBB4 signaling / mammary gland epithelial cell differentiation / negative regulation of epithelial cell apoptotic process / embryonic pattern specification / transmembrane receptor protein tyrosine kinase activator activity / positive regulation of urine volume / positive regulation of protein localization to cell surface / neural crest cell migration / epidermal growth factor receptor binding / epithelial cell apoptotic process / Inhibition of Signaling by Overexpressed EGFR / EGFR interacts with phospholipase C-gamma / positive regulation of tyrosine phosphorylation of STAT protein / neurotransmitter receptor localization to postsynaptic specialization membrane / ERBB2-EGFR signaling pathway / ERBB2 Activates PTK6 Signaling / Signaling by EGFR / ERBB2 Regulates Cell Motility / Signaling by ERBB4 / Long-term potentiation / positive regulation of cell division / PI3K events in ERBB2 signaling / mammary gland alveolus development / SHC1 events in ERBB4 signaling / cell surface receptor signaling pathway via JAK-STAT / cell fate commitment / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / GAB1 signalosome / Nuclear signaling by ERBB4 / synapse assembly / positive regulation of cardiac muscle cell proliferation / Signaling by ERBB2 / transmembrane receptor protein tyrosine kinase activity / lactation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / GRB2 events in ERBB2 signaling / positive regulation of mitotic nuclear division / Downregulation of ERBB4 signaling / SHC1 events in ERBB2 signaling / cellular response to epidermal growth factor stimulus / cell surface receptor protein tyrosine kinase signaling pathway / regulation of cell migration / positive regulation of epithelial cell proliferation / basal plasma membrane / GABA-ergic synapse / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of cell differentiation / growth factor activity / EGFR downregulation / Signaling by ERBB2 TMD/JMD mutants / clathrin-coated endocytic vesicle membrane / placental growth factor receptor activity / postsynaptic density membrane / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / neuromuscular junction / peptidyl-tyrosine phosphorylation / Signaling by ERBB2 KD Mutants / epidermal growth factor receptor signaling pathway / Downregulation of ERBB2 signaling / positive regulation of fibroblast proliferation / neuron differentiation / Constitutive Signaling by Aberrant PI3K in Cancer / cell migration / nervous system development / Cargo recognition for clathrin-mediated endocytosis / PIP3 activates AKT signaling / Clathrin-mediated endocytosis / positive regulation of protein phosphorylation / presynaptic membrane / heart development / RAF/MAP kinase cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein autophosphorylation
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 / 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
Probetacellulin / Receptor tyrosine-protein kinase erbB-4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 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 16681/1 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 9, 2024-
Current statusOct 9, 2024Processing site: RCSB / Status: Released

-
Structure visualization

Supplemental images

emd_41884.png

Downloads & links

-
Map

FileDownload / File: emd_41884.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.835 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0688
Minimum - Maximum-1.0865064 - 1.6778605
Average (Standard dev.)-0.00041947208 (±0.029769713)
SymmetrySpace group: 1
Details

EMDB XML:

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

-
Supplemental data

-
Mask #1

Fileemd_41884_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_41884_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_41884_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
Entire : HER4/BTC homodimer

EntireName: HER4/BTC homodimer
Components
  • Complex: HER4/BTC homodimer
    • Protein or peptide: Receptor tyrosine-protein kinase erbB-4
    • Protein or peptide: Betacellulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

-
Supramolecule #1: HER4/BTC homodimer

SupramoleculeName: HER4/BTC homodimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 306.694 KDa

-
Macromolecule #1: Receptor tyrosine-protein kinase erbB-4

MacromoleculeName: Receptor tyrosine-protein kinase erbB-4 / 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: 68.07282 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 TSHDCIY

UniProtKB: Receptor tyrosine-protein kinase erbB-4

-
Macromolecule #2: Betacellulin

MacromoleculeName: Betacellulin / type: protein_or_peptide / ID: 2 / Number of copies: 2 / 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

-
Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
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

-
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

+
Image processing

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

3u7u


Details: The initial model for the ligand was obtained from the AlphaFoldDB (AF-P35070-F1) and aligned to 3U7U using UCSF ChimeraX.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 2.15) / Number images used: 274540
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)

-
Atomic model buiding 1

Initial modelPDB ID:

3u7u


Chain - Source name: PDB / Chain - Initial model type: experimental model
Output model

PDB-8u4j:
Structure of the HER4/BTC Homodimer Extracellular Domain

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more