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- PDB-9fk5: Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3... -

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Basic information

Entry
Database: PDB / ID: 9fk5
TitleZebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRII
Components
  • (Transforming growth factor beta-3) x 2
  • TGF-beta receptor type-1
  • TGF-beta receptor type-2
  • Transforming growth factor beta receptor III
KeywordsMEMBRANE PROTEIN / Complex / Betaglycan / TGFBR3 / TGFb / TGFBR1 / TGFBR2
Function / homology
Function and homology information


FGFR1b ligand binding and activation / FGFR1c ligand binding and activation / TGF-beta receptor signaling activates SMADs / TGFBR3 PTM regulation / TGFBR3 regulates TGF-beta signaling / TGFBR3 regulates FGF2 signaling / positive regulation of tolerance induction to self antigen / positive regulation of B cell tolerance induction / uterine wall breakdown / inferior endocardial cushion morphogenesis ...FGFR1b ligand binding and activation / FGFR1c ligand binding and activation / TGF-beta receptor signaling activates SMADs / TGFBR3 PTM regulation / TGFBR3 regulates TGF-beta signaling / TGFBR3 regulates FGF2 signaling / positive regulation of tolerance induction to self antigen / positive regulation of B cell tolerance induction / uterine wall breakdown / inferior endocardial cushion morphogenesis / bronchus morphogenesis / mammary gland morphogenesis / detection of hypoxia / lens fiber cell apoptotic process / growth plate cartilage chondrocyte growth / tricuspid valve morphogenesis / frontal suture morphogenesis / activin receptor activity / extracellular structure organization / epicardium morphogenesis / vascular endothelial cell proliferation / TGFBR2 MSI Frameshift Mutants in Cancer / embryonic neurocranium morphogenesis / miRNA transport / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / type III transforming growth factor beta receptor binding / aorta morphogenesis / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / Langerhans cell differentiation / negative regulation of macrophage cytokine production / TGFBR2 Kinase Domain Mutants in Cancer / ventricular compact myocardium morphogenesis / transforming growth factor beta receptor activity / cardiac left ventricle morphogenesis / regulation of transforming growth factor beta receptor signaling pathway / positive regulation of mesenchymal stem cell proliferation / secondary palate development / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / endocardial cushion fusion / positive regulation of T cell tolerance induction / membranous septum morphogenesis / TGFBR3 regulates TGF-beta signaling / lung lobe morphogenesis / response to laminar fluid shear stress / regulation of epithelial to mesenchymal transition / positive regulation of tight junction disassembly / activin receptor complex / positive regulation of NK T cell differentiation / cardiac epithelial to mesenchymal transition / somite development / positive regulation of vasculature development / neuron fate commitment / mesenchymal cell differentiation / positive regulation of extracellular matrix assembly / transforming growth factor beta receptor activity, type I / type II transforming growth factor beta receptor binding / activin receptor activity, type I / activin receptor activity, type II / angiogenesis involved in coronary vascular morphogenesis / BMP receptor activity / receptor protein serine/threonine kinase / transforming growth factor beta receptor activity, type II / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / regulation of stem cell proliferation / transforming growth factor beta receptor activity, type III / TGFBR1 LBD Mutants in Cancer / myeloid dendritic cell differentiation / activin binding / coronary artery morphogenesis / germ cell migration / type I transforming growth factor beta receptor binding / SMAD protein signal transduction / pattern specification process / activin receptor signaling pathway / ventricular trabecula myocardium morphogenesis / filopodium assembly / positive regulation of CD4-positive, alpha-beta T cell proliferation / mammary gland development / outflow tract septum morphogenesis / glycosaminoglycan binding / cell-cell junction organization / regulation of stem cell differentiation / response to cholesterol / kinase activator activity / embryonic cranial skeleton morphogenesis / I-SMAD binding / transforming growth factor beta binding / negative regulation of chondrocyte differentiation / digestive tract development / collagen fibril organization / aortic valve morphogenesis / sprouting angiogenesis / face morphogenesis / lens development in camera-type eye / embryonic hemopoiesis
Similarity search - Function
Transforming growth factor beta-3 / 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. / Zona pellucida, ZP-C domain / ZP-C domain / Zona pellucida (ZP) domain / Transforming growth factor-beta ...Transforming growth factor beta-3 / 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. / Zona pellucida, ZP-C domain / ZP-C domain / Zona pellucida (ZP) domain / Transforming growth factor-beta / 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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsWieteska, L. / Coleman, J.A. / Hinck, A.P.
Funding support United States, European Union, 2items
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, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 12, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transforming growth factor beta-3
B: Transforming growth factor beta-3
C: TGF-beta receptor type-1
D: TGF-beta receptor type-2
E: Transforming growth factor beta receptor III


Theoretical massNumber of molelcules
Total (without water)85,4495
Polymers85,4495
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Transforming growth factor beta-3 / TGF-beta-3


Mass: 12734.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB3 / Production host: Escherichia coli (E. coli) / References: UniProt: P10600
#2: Protein Transforming growth factor beta-3 / TGF-beta-3


Mass: 12586.247 Da / Num. of mol.: 1 / Mutation: R325E,Y390A,R394E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB3 / Production host: Escherichia coli (E. coli) / References: UniProt: P10600
#3: Protein TGF-beta receptor type-1 / TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ...TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ALK-5 / ALK5 / Serine/threonine-protein kinase receptor R4 / SKR4 / TGF-beta type I receptor / Transforming growth factor-beta receptor type I / TGF-beta receptor type I / TbetaR-I


Mass: 9474.826 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, ALK5, SKR4 / Production host: Escherichia coli (E. coli)
References: UniProt: P36897, receptor protein serine/threonine kinase
#4: Protein TGF-beta receptor type-2 / TGFR-2 / TGF-beta type II receptor / Transforming growth factor-beta receptor type II / TGF-beta ...TGFR-2 / TGF-beta type II receptor / Transforming growth factor-beta receptor type II / TGF-beta receptor type II / TbetaR-II


Mass: 12926.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR2 / Production host: Escherichia coli (E. coli)
References: UniProt: P37173, receptor protein serine/threonine kinase
#5: Protein Transforming growth factor beta receptor III / Transforming growth factor beta receptor type 3 precursor


Mass: 37727.000 Da / Num. of mol.: 1 / Mutation: C150G,C277G
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: tgfbr3, si:ch73-18k18.1 / Production host: Homo sapiens (human) / References: UniProt: A0A0H3UK16
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

Component
IDNameTypeEntity IDParent-IDSource
1Quinary complex of Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-B3 and extracellular domains of TGFBRI and TGFBRIICOMPLEXall0MULTIPLE SOURCES
2Zebrafish Betaglycan - Orphan domainCOMPLEX#51RECOMBINANT
3complex part - TGF-B3 and extracellular domains of TGFBRI and TGFBRIICOMPLEX#1-#41RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.09 MDaYES
22
33
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Danio rerio (zebrafish)7955
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Escherichia coli (E. coli)562
32Homo sapiens (human)9606
43Escherichia coli (E. coli)562
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPESC8H18N2O4S1
2150 mMsodium chlorideNaCl1
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 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: 2500 nm / Nominal defocus min: 750 nm / Alignment procedure: COMA FREE
Image recordingElectron dose: 45 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraX1.7model fitting
9PHENIX1.21model refinement
13cryoSPARC43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 281881 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 9B9F

9b9f


Accession code: 9B9F / Source name: PDB / Type: experimental model

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