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- PDB-9fkp: Zebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1... -

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Basic information

Entry
Database: PDB / ID: 9fkp
TitleZebrafish Betaglycan Orphan Domain (zfBGo) in complex with TGF-b1 and extracellular domain of TGFBRII
Components
  • TGF-beta receptor type-2
  • Transforming growth factor beta receptor III
  • Transforming growth factor beta-1
KeywordsMEMBRANE PROTEIN / Complex / Betaglycan / TGFBR3 / TGFb / TGFBR1 / TGFBR2
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 / transforming growth factor beta complex / positive regulation of primary miRNA processing / morphogenesis of a branching structure / negative regulation of skeletal muscle tissue development / response to laminar fluid shear stress / tricuspid valve morphogenesis / embryonic liver development / macrophage derived foam cell differentiation / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / positive regulation of T cell tolerance induction / miRNA transport / regulation of protein import into nucleus / regulation of blood vessel remodeling / cellular response to acetaldehyde / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / extracellular matrix assembly / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / aorta morphogenesis / myofibroblast differentiation / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / negative regulation of macrophage cytokine production / connective tissue replacement involved in inflammatory response wound healing / transforming growth factor beta receptor activity / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of exit from mitosis / cardiac left ventricle morphogenesis / regulation of transforming growth factor beta receptor signaling pathway / secondary palate development / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / odontoblast differentiation / positive regulation of mesenchymal stem cell proliferation / endocardial cushion fusion / positive regulation of receptor signaling pathway via STAT / membrane protein intracellular domain proteolysis / positive regulation of isotype switching to IgA isotypes / positive regulation of extracellular matrix assembly / positive regulation of NK T cell differentiation / somite development / membranous septum morphogenesis / heart valve morphogenesis / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / hyaluronan catabolic process / activin receptor activity, type I / activin receptor complex / ATP biosynthetic process / negative regulation of extracellular matrix disassembly / type II transforming growth factor beta receptor binding / receptor protein serine/threonine kinase / activin binding / myeloid dendritic cell differentiation / positive regulation of branching involved in ureteric bud morphogenesis / transmembrane receptor protein serine/threonine kinase activity / receptor catabolic process / positive regulation of cardiac muscle cell differentiation / TGFBR1 LBD Mutants in Cancer / cell-cell junction organization / negative regulation of myoblast differentiation / response to salt / regulatory T cell differentiation / embryonic cranial skeleton morphogenesis / negative regulation of cell-cell adhesion mediated by cadherin / glycosaminoglycan binding / activin receptor signaling pathway / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / positive regulation of CD4-positive, alpha-beta T cell proliferation / positive regulation of chemotaxis / positive regulation of vascular permeability / positive regulation of mononuclear cell migration / outflow tract septum morphogenesis / oligodendrocyte development / regulation of stem cell differentiation / embryonic hemopoiesis / negative regulation of interleukin-17 production / phosphate-containing compound metabolic process / sprouting angiogenesis / response to cholesterol / positive regulation of mesenchymal cell proliferation
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.72 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 3, 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-1
B: Transforming growth factor beta-1
D: TGF-beta receptor type-2
E: TGF-beta receptor type-2
C: Transforming growth factor beta receptor III


Theoretical massNumber of molelcules
Total (without water)89,2005
Polymers89,2005
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-1 / TGF-beta-1


Mass: 12809.812 Da / Num. of mol.: 2 / Fragment: Mature
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB1, TGFB / Production host: Escherichia coli (E. coli) / References: UniProt: P01137
#2: 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.: 2
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
#3: 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-B1 and extracellular domains of TGFBRIICOMPLEXall0MULTIPLE SOURCES
2Zebrafish Betaglycan - Orphan domainCOMPLEX#31RECOMBINANT
3complex part - TGF-B1 and extracellular domains TGFBRIICOMPLEX#1-#21RECOMBINANT
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 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
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.72 Å / Resolution method: FSC 0.5 CUT-OFF / Num. of particles: 307870 / 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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