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- EMDB-50524: Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1... -

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Basic information

Entry
Database: EMDB / ID: EMD-50524
TitleZebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1 and extracellular domain of TGFBRII
Map dataGaussian blurred
Sample
  • Complex: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B1 and extracellular domains of TGFBRII
    • Complex: Zebrafish Betaglycan - Orphan domain
      • Protein or peptide: Transforming growth factor beta receptor III
    • Complex: complex part - TGF-B1 and extracellular domains TGFBRII
      • Protein or peptide: Transforming growth factor beta-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 / positive regulation of tolerance induction to self antigen ...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 / 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 / frontal suture morphogenesis / Influenza Virus Induced Apoptosis / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / positive regulation of microglia differentiation / regulation of interleukin-23 production / positive regulation of primary miRNA processing / morphogenesis of a branching structure / negative regulation of skeletal muscle tissue development / embryonic liver development / regulation of striated muscle tissue development / tricuspid valve morphogenesis / response to laminar fluid shear stress / heart valve morphogenesis / macrophage derived foam cell differentiation / TGFBR2 MSI Frameshift Mutants in Cancer / miRNA transport / positive regulation of T cell tolerance induction / negative regulation of MyD88-dependent toll-like receptor signaling pathway / aorta morphogenesis / regulation of protein import into nucleus / transforming growth factor beta complex / regulation of blood vessel remodeling / transforming growth factor beta ligand-receptor complex / negative regulation of macrophage cytokine production / cellular response to acetaldehyde / connective tissue replacement involved in inflammatory response wound healing / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of hyaluronan biosynthetic process / extracellular matrix assembly / 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 / odontoblast differentiation / cardiac left ventricle morphogenesis / positive regulation of exit from mitosis / salivary gland morphogenesis / membranous septum morphogenesis / somite development / negative regulation of neuroblast proliferation / positive regulation of isotype switching to IgA isotypes / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / secondary palate development / myeloid dendritic cell differentiation / positive regulation of CD4-positive, alpha-beta T cell proliferation / endocardial cushion fusion / positive regulation of NK T cell differentiation / positive regulation of mesenchymal stem cell proliferation / positive regulation of receptor signaling pathway via STAT / membrane protein intracellular domain proteolysis / positive regulation of extracellular matrix assembly / ATP biosynthetic process / negative regulation of myoblast differentiation / TGFBR3 regulates TGF-beta signaling / neural tube development / positive regulation of vasculature development / activin receptor activity, type I / activin receptor complex / hyaluronan catabolic process / positive regulation of mesenchymal cell proliferation / cell-cell junction organization / receptor protein serine/threonine kinase / type II transforming growth factor beta receptor binding / activin binding / negative regulation of extracellular matrix disassembly / embryonic cranial skeleton morphogenesis / transmembrane receptor protein serine/threonine kinase activity / positive regulation of branching involved in ureteric bud morphogenesis / receptor catabolic process / response to salt / positive regulation of cardiac muscle cell differentiation / TGFBR1 LBD Mutants in Cancer / atrioventricular valve morphogenesis / regulatory T cell differentiation / negative regulation of cell-cell adhesion mediated by cadherin / glycosaminoglycan binding / positive regulation of chemotaxis / regulation of stem cell differentiation / activin receptor signaling pathway / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / ureteric bud development / positive regulation of vascular permeability / outflow tract septum morphogenesis
Similarity search - Function
: / 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 / Transforming growth factor beta-1 proprotein / Zona pellucida domain, conserved site / ZP domain signature. / Transforming growth factor-beta / : ...: / 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 / Transforming growth factor beta-1 proprotein / 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 / TGF-beta, propeptide / TGF-beta propeptide / 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. / 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-1 proprotein / TGF-beta receptor type-2
Similarity search - Component
Biological speciesHomo sapiens (human) / Danio rerio (zebrafish)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.72 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 3, 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_50524.png

Downloads & links

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Map

FileDownload / File: emd_50524.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationGaussian blurred
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.72 Å/pix.
x 384 pix.
= 276.48 Å		0.72 Å/pix.
x 384 pix.
= 276.48 Å		0.72 Å/pix.
x 384 pix.
= 276.48 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.72 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.035
Minimum - Maximum-0.21748315 - 0.42456985
Average (Standard dev.)-0.00011064358 (±0.006152978)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharpened map

Fileemd_50524_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Histogram

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Additional map: EMReady enhanced

Fileemd_50524_additional_2.map
AnnotationEMReady enhanced
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map

Fileemd_50524_half_map_1.map
Annotationhalf map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map

Fileemd_50524_half_map_2.map
Annotationhalf map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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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-B1 and extracellular domains of TGFBRII
Components
  • Complex: Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B1 and extracellular domains of TGFBRII
    • Complex: Zebrafish Betaglycan - Orphan domain
      • Protein or peptide: Transforming growth factor beta receptor III
    • Complex: complex part - TGF-B1 and extracellular domains TGFBRII
      • Protein or peptide: Transforming growth factor beta-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-B1 and extracellular domains of 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: #3
Source (natural)Organism: Danio rerio (zebrafish)

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Supramolecule #3: complex part - TGF-B1 and extracellular domains TGFBRII

SupramoleculeName: complex part - TGF-B1 and extracellular domains TGFBRII
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transforming growth factor beta-1

MacromoleculeName: Transforming growth factor beta-1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 12.809812 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
ALDTNYCFSS TEKNCCVRQL YIDFRKDLGW KWIHEPKGYH ANFCLGPCPY IWSLDTQYSK VLALYNQHNP GASAAPCCVP QALEPLPIV YYVGRKPKVE QLSNMIVRSC KCS

UniProtKB: Transforming growth factor beta-1 proprotein

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Macromolecule #2: TGF-beta receptor type-2

MacromoleculeName: TGF-beta receptor type-2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / 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 #3: Transforming growth factor beta receptor III

MacromoleculeName: Transforming growth factor beta receptor III / type: protein_or_peptide / ID: 3 / 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 / Support film - Material: GOLD / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE
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: 3.72 Å / Resolution method: FSC 0.5 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0) / Number images used: 307870
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC
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-9fkp:
Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1 and extracellular domain of TGFBRII

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