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- EMDB-50519: Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3... -

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Entry
Database: EMDB / ID: EMD-50519
TitleZebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
Map data
Sample
  • Complex: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
    • Complex: Zebrafish Betaglycan - Orphan domain
      • Protein or peptide: Transforming growth factor beta receptor III
    • Complex: complex part - TGF-B3 and extracellular domains of TGFBRI and TGFBRII
      • Protein or peptide: Transforming growth factor beta-3
      • Protein or peptide: Transforming growth factor beta-3
      • Protein or peptide: TGF-beta receptor type-1
      • Protein or peptide: TGF-beta receptor type-2
KeywordsComplex / Betaglycan / TGFBR3 / TGFb / TGFBR1 / TGFBR2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


Signaling by Activin / FGFR1b ligand binding and activation / FGFR1c ligand binding and activation / Signaling by BMP / TGF-beta receptor signaling activates SMADs / TGFBR3 PTM regulation / TGFBR3 regulates TGF-beta signaling / TGFBR3 regulates FGF2 signaling / TGFBR3 regulates activin signaling / uterine wall breakdown ...Signaling by Activin / FGFR1b ligand binding and activation / FGFR1c ligand binding and activation / Signaling by BMP / TGF-beta receptor signaling activates SMADs / TGFBR3 PTM regulation / TGFBR3 regulates TGF-beta signaling / TGFBR3 regulates FGF2 signaling / TGFBR3 regulates activin signaling / uterine wall breakdown / positive regulation of tolerance induction to self antigen / positive regulation of B cell tolerance induction / inferior endocardial cushion morphogenesis / transforming growth factor beta receptor activity, type II / detection of hypoxia / extracellular structure organization / epicardium morphogenesis / tricuspid valve morphogenesis / vascular endothelial cell proliferation / TGFBR2 MSI Frameshift Mutants in Cancer / parathyroid gland development / miRNA transport / positive regulation of T cell tolerance induction / aorta morphogenesis / transforming growth factor beta complex / regulation of cardiac muscle cell proliferation / negative regulation of macrophage cytokine production / type III transforming growth factor beta receptor binding / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / myofibroblast differentiation / regulation of transforming growth factor beta receptor signaling pathway / transforming growth factor beta receptor activity / TGFBR2 Kinase Domain Mutants in Cancer / cardiac left ventricle morphogenesis / trophoblast cell migration / pharyngeal system development / membranous septum morphogenesis / secondary palate development / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / angiogenesis involved in coronary vascular morphogenesis / somite development / positive regulation of CD4-positive, alpha-beta T cell proliferation / positive regulation of mesenchymal stem cell proliferation / endocardial cushion fusion / positive regulation of NK T cell differentiation / ventricular compact myocardium morphogenesis / positive regulation of tight junction disassembly / positive regulation of extracellular matrix assembly / mesenchymal cell differentiation / cardiac epithelial to mesenchymal transition / transforming growth factor beta receptor activity, type I / neuron fate commitment / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / activin receptor activity, type I / activin receptor complex / primordial germ cell migration / regulation of epithelial to mesenchymal transition / myeloid dendritic cell differentiation / positive regulation of mesenchymal cell proliferation / receptor protein serine/threonine kinase / type II transforming growth factor beta receptor binding / activin binding / cell-cell junction organization / embryonic cranial skeleton morphogenesis / anterior/posterior pattern specification / transmembrane receptor protein serine/threonine kinase activity / TGFBR1 LBD Mutants in Cancer / mammary gland development / coronary artery morphogenesis / ventricular trabecula myocardium morphogenesis / glycosaminoglycan binding / lung alveolus development / regulation of stem cell differentiation / activin receptor signaling pathway / type I transforming growth factor beta receptor binding / outflow tract septum morphogenesis / collagen fibril organization / artery morphogenesis / negative regulation of chondrocyte differentiation / branching involved in blood vessel morphogenesis / embryonic hemopoiesis / face morphogenesis / sprouting angiogenesis / response to cholesterol / transforming growth factor beta binding / cartilage development / odontogenesis / I-SMAD binding / skeletal system morphogenesis / positive regulation of filopodium assembly / atrioventricular valve morphogenesis / aortic valve morphogenesis / kinase activator activity / endothelial cell activation / Molecules associated with elastic fibres / roof of mouth development / ventricular septum morphogenesis / blood vessel development
Similarity search - Function
Transforming growth factor beta-3 / : / TGFBR3-like, N-terminal domain / Transforming growth factor beta receptor 2 ectodomain / Transforming growth factor-beta receptor, type II / Transforming growth factor beta receptor 2 ectodomain / Zona pellucida domain, conserved site / ZP domain signature. / Transforming growth factor-beta / : ...Transforming growth factor beta-3 / : / TGFBR3-like, N-terminal domain / Transforming growth factor beta receptor 2 ectodomain / Transforming growth factor-beta receptor, type II / Transforming growth factor beta receptor 2 ectodomain / Zona pellucida domain, conserved site / ZP domain signature. / Transforming growth factor-beta / : / : / ZP-N domain / Zona pellucida, ZP-C domain / ZP-C domain / Zona pellucida (ZP) domain / ZP domain profile. / Zona pellucida domain / GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / TGF-beta, propeptide / TGF-beta propeptide / Activin types I and II receptor domain / Activin types I and II receptor domain / Transforming growth factor beta, conserved site / TGF-beta family signature. / Transforming growth factor-beta-related / Transforming growth factor-beta (TGF-beta) family / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Ser/Thr protein kinase, TGFB receptor / Cystine-knot cytokine / Snake toxin-like superfamily / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, 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
Transforming growth factor beta receptor III / Transforming growth factor beta-3 proprotein / TGF-beta receptor type-1 / TGF-beta receptor type-2
Similarity search - Component
Biological speciesHomo sapiens (human) / Danio rerio (zebrafish)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsWieteska L / Coleman JA / Hinck AP
Funding support United States, European Union, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM058670 United States
H2020 Marie Curie Actions of the European Commission893196European Union
CitationJournal: Nat Commun / Year: 2025
Title: Structures of TGF-β with betaglycan and signaling receptors reveal mechanisms of complex assembly and signaling.
Authors: Łukasz Wieteska / Alexander B Taylor / Emma Punch / Jonathan A Coleman / Isabella O Conway / Yeu-Farn Lin / Chang-Hyeock Byeon / Cynthia S Hinck / Troy Krzysiak / Rieko Ishima / Fernando ...Authors: Łukasz Wieteska / Alexander B Taylor / Emma Punch / Jonathan A Coleman / Isabella O Conway / Yeu-Farn Lin / Chang-Hyeock Byeon / Cynthia S Hinck / Troy Krzysiak / Rieko Ishima / Fernando López-Casillas / Peter Cherepanov / Daniel J Bernard / Caroline S Hill / Andrew P Hinck /
Abstract: Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility ...Betaglycan (BG) is a transmembrane co-receptor of the transforming growth factor-β (TGF-β) family of signaling ligands. It is essential for embryonic development, tissue homeostasis and fertility in adults. It functions by enabling binding of the three TGF-β isoforms to their signaling receptors and is additionally required for inhibin A (InhA) activity. Despite its requirement for the functions of TGF-βs and InhA in vivo, structural information explaining BG ligand selectivity and its mechanism of action is lacking. Here, we determine the structure of TGF-β bound both to BG and the signaling receptors, TGFBR1 and TGFBR2. We identify key regions responsible for ligand engagement, which has revealed binding interfaces that differ from those described for the closely related co-receptor of the TGF-β family, endoglin, thus demonstrating remarkable evolutionary adaptation to enable ligand selectivity. Finally, we provide a structural explanation for the hand-off mechanism underlying TGF-β signal potentiation.
History
DepositionJun 2, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateMar 12, 2025-
Current statusMar 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50519.png

Downloads & links

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Map

FileDownload / File: emd_50519.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.)
0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å		0.83 Å/pix.
x 384 pix.
= 318.72 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.193
Minimum - Maximum-0.61481357 - 1.3156903
Average (Standard dev.)-0.00013211218 (±0.016207779)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 318.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #2

Fileemd_50519_additional_1.map
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Additional map: #1

Fileemd_50519_additional_2.map
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Half map: #2

Fileemd_50519_half_map_1.map
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Half map: #1

Fileemd_50519_half_map_2.map
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Sample components

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Entire : Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in ...

EntireName: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
Components
  • Complex: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
    • Complex: Zebrafish Betaglycan - Orphan domain
      • Protein or peptide: Transforming growth factor beta receptor III
    • Complex: complex part - TGF-B3 and extracellular domains of TGFBRI and TGFBRII
      • Protein or peptide: Transforming growth factor beta-3
      • Protein or peptide: Transforming growth factor beta-3
      • Protein or peptide: TGF-beta receptor type-1
      • Protein or peptide: TGF-beta receptor type-2

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Supramolecule #1: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in ...

SupramoleculeName: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 90 KDa

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Supramolecule #2: Zebrafish Betaglycan - Orphan domain

SupramoleculeName: Zebrafish Betaglycan - Orphan domain / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Danio rerio (zebrafish)

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Supramolecule #3: complex part - TGF-B3 and extracellular domains of TGFBRI and TGFBRII

SupramoleculeName: complex part - TGF-B3 and extracellular domains of TGFBRI and TGFBRII
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transforming growth factor beta-3

MacromoleculeName: Transforming growth factor beta-3 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.734504 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ALDTNYCFRN LEENCCVRPL YIDFRQDLGW KWVHEPKGYY ANFCSGPCPY LRSADTTHST VLGLYNTLNP EASASPCCVP QDLEPLTIL YYVGRTPKVE QLSNMVVKSC KCS

UniProtKB: Transforming growth factor beta-3 proprotein

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Macromolecule #2: Transforming growth factor beta-3

MacromoleculeName: Transforming growth factor beta-3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.586247 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ALDTNYCFRN LEENCCVRPL YIDFEQDLGW KWVHEPKGYY ANFCSGPCPY LRSADTTHST VLGLYNTLNP EASASPCCVP QDLEPLTIL AYVGETPKVE QLSNMVVKSC KCS

UniProtKB: Transforming growth factor beta-3 proprotein

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Macromolecule #3: TGF-beta receptor type-1

MacromoleculeName: TGF-beta receptor type-1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein serine/threonine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 9.474826 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
GSATALQCFC HLCTKDNFTC VTDGLCFVSV TETTDKVIHN SMCIAEIDLI PRDRPFVCAP SSKTGSVTTT YCCNQDHCNK IELPTTV

UniProtKB: TGF-beta receptor type-1

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Macromolecule #4: TGF-beta receptor type-2

MacromoleculeName: TGF-beta receptor type-2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein serine/threonine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.926812 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MNGAVKFPQL CKFCDVRFST CDNQKSCMSN CSITSICEKP QEVCVAVWRK NDENITLETV CHDPKLPYHD FILEDAASPK CIMKEKKKP GETFFMCSCS SDECNDNIIF SEEY

UniProtKB: TGF-beta receptor type-2

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Macromolecule #5: Transforming growth factor beta receptor III

MacromoleculeName: Transforming growth factor beta receptor III / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Danio rerio (zebrafish)
Molecular weightTheoretical: 37.727 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GSPCELLPVG VGHPVQAMLK SFTALSGCAS RGTTSHPQEV HIINLRKGSA QGAREKTAEV ALHLRPIQSL HVHQKPLVFI LNSPQPILW KVRTEKLAPG VKRIFHVVEG SEVHFEVGNF SKSGEVKVET LPHGNEHLLN WAHHRYTAVT SFSELRMAHD I YIKVGEDP ...String:
GSPCELLPVG VGHPVQAMLK SFTALSGCAS RGTTSHPQEV HIINLRKGSA QGAREKTAEV ALHLRPIQSL HVHQKPLVFI LNSPQPILW KVRTEKLAPG VKRIFHVVEG SEVHFEVGNF SKSGEVKVET LPHGNEHLLN WAHHRYTAVT SFSELRMAHD I YIKVGEDP VFSETCKIDN KFLSLNYLAS YIEPQPSTGC VLSGPDHEQE VHIIELQAPN SSSAFQVDVI VDLRPLDGDI PL HRDVVLL LKGEKSVNWV IKAHKVMGKL EIMTSDTVSL SEDTERLMQV SKTVKQKLPA GSQALIQWAE ENGFNPVTSY TNT PVANHF NLRLREHHHH HH

UniProtKB: Transforming growth factor beta receptor III

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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

Concentration0.3 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
150.0 mMNaClsodium chloride
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.75 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:

9b9f

Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.1 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0) / Number images used: 281881
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

9b9f


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-9fk5:
Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII

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