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- PDB-8vs6: L-TGF-b3/avb8 -

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Basic information

Entry
Database: PDB / ID: 8vs6
TitleL-TGF-b3/avb8
Components
  • Integrin alpha-V
  • Integrin beta-8
  • Transforming growth factor beta-3 proprotein
KeywordsSIGNALING PROTEIN / TGFb / Complex
Function / homology
Function and homology information


ganglioside metabolic process / uterine wall breakdown / detection of hypoxia / type III transforming growth factor beta receptor binding / Langerhans cell differentiation / secondary palate development / negative regulation of macrophage cytokine production / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production ...ganglioside metabolic process / uterine wall breakdown / detection of hypoxia / type III transforming growth factor beta receptor binding / Langerhans cell differentiation / secondary palate development / negative regulation of macrophage cytokine production / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / positive regulation of tight junction disassembly / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / type II transforming growth factor beta receptor binding / placenta blood vessel development / Laminin interactions / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / type I transforming growth factor beta receptor binding / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / alphav-beta3 integrin-HMGB1 complex / negative regulation of lipid transport / hard palate development / regulation of phagocytosis / mammary gland development / Elastic fibre formation / cell-cell junction organization / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / positive regulation of small GTPase mediated signal transduction / cartilage development / filopodium membrane / extracellular matrix binding / negative regulation of low-density lipoprotein particle clearance / apolipoprotein A-I-mediated signaling pathway / apoptotic cell clearance / face morphogenesis / wound healing, spreading of epidermal cells / odontogenesis / positive regulation of filopodium assembly / integrin complex / heterotypic cell-cell adhesion / Molecules associated with elastic fibres / negative chemotaxis / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / lung alveolus development / Syndecan interactions / cell adhesion mediated by integrin / positive regulation of osteoblast proliferation / microvillus membrane / cell-substrate adhesion / endodermal cell differentiation / PECAM1 interactions / TGF-beta receptor signaling activates SMADs / positive regulation of intracellular signal transduction / positive regulation of collagen biosynthetic process / negative regulation of vascular associated smooth muscle cell proliferation / fibronectin binding / lamellipodium membrane / positive regulation of cell division / positive regulation of SMAD protein signal transduction / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / positive regulation of epithelial to mesenchymal transition / vasculogenesis / salivary gland morphogenesis / voltage-gated calcium channel activity / specific granule membrane / coreceptor activity / phagocytic vesicle / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of cell adhesion / substrate adhesion-dependent cell spreading / transforming growth factor beta receptor signaling pathway / protein kinase C binding / response to progesterone / platelet alpha granule lumen / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / cell-matrix adhesion / cytokine activity / Signal transduction by L1 / integrin-mediated signaling pathway / positive regulation of protein secretion / negative regulation of extrinsic apoptotic signaling pathway / growth factor activity / cell-cell adhesion / calcium ion transmembrane transport / VEGFA-VEGFR2 Pathway / response to virus / ruffle membrane / integrin binding
Similarity search - Function
Transforming growth factor beta-3 / Transforming growth factor-beta / Teneurin-like EGF 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-3 / Transforming growth factor-beta / Teneurin-like EGF 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. / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin alpha cytoplasmic region / Integrins beta chain EGF (I-EGF) domain profile. / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain EGF (I-EGF) domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / Integrin alpha chain / Integrin alpha beta-propellor / : / Integrin alpha Ig-like domain 2 / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin alpha, N-terminal / Integrin domain superfamily / Cystine-knot cytokine / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain
Similarity search - Domain/homology
Integrin alpha-V / Transforming growth factor beta-3 proprotein / Integrin beta-8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsJin, M. / Cheng, Y. / Nishimura, S.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL134183 United States
CitationJournal: Cell / Year: 2024
Title: Dynamic allostery drives autocrine and paracrine TGF-β signaling.
Authors: Mingliang Jin / Robert I Seed / Guoqing Cai / Tiffany Shing / Li Wang / Saburo Ito / Anthony Cormier / Stephanie A Wankowicz / Jillian M Jespersen / Jody L Baron / Nicholas D Carey / Melody ...Authors: Mingliang Jin / Robert I Seed / Guoqing Cai / Tiffany Shing / Li Wang / Saburo Ito / Anthony Cormier / Stephanie A Wankowicz / Jillian M Jespersen / Jody L Baron / Nicholas D Carey / Melody G Campbell / Zanlin Yu / Phu K Tang / Pilar Cossio / Weihua Wen / Jianlong Lou / James Marks / Stephen L Nishimura / Yifan Cheng /
Abstract: TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association ...TGF-β, essential for development and immunity, is expressed as a latent complex (L-TGF-β) non-covalently associated with its prodomain and presented on immune cell surfaces by covalent association with GARP. Binding to integrin αvβ8 activates L-TGF-β1/GARP. The dogma is that mature TGF-β must physically dissociate from L-TGF-β1 for signaling to occur. Our previous studies discovered that αvβ8-mediated TGF-β autocrine signaling can occur without TGF-β1 release from its latent form. Here, we show that mice engineered to express TGF-β1 that cannot release from L-TGF-β1 survive without early lethal tissue inflammation, unlike those with TGF-β1 deficiency. Combining cryogenic electron microscopy with cell-based assays, we reveal a dynamic allosteric mechanism of autocrine TGF-β1 signaling without release where αvβ8 binding redistributes the intrinsic flexibility of L-TGF-β1 to expose TGF-β1 to its receptors. Dynamic allostery explains the TGF-β3 latency/activation mechanism and why TGF-β3 functions distinctly from TGF-β1, suggesting that it broadly applies to other flexible cell surface receptor/ligand systems.
History
DepositionJan 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Nov 13, 2024Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _em_admin.last_update
Revision 1.4Nov 20, 2024Group: Data collection / Database references / Category: citation / em_admin / Item: _citation.page_last / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Transforming growth factor beta-3 proprotein
A: Integrin alpha-V
B: Integrin beta-8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)226,16417
Polymers222,5053
Non-polymers3,65914
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 3 types, 3 molecules EAB

#1: Protein Transforming growth factor beta-3 proprotein


Mass: 44858.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB3 / Production host: Homo sapiens (human) / References: UniProt: P10600
#2: Protein Integrin alpha-V / Vitronectin receptor / Vitronectin receptor subunit alpha


Mass: 106375.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAV, MSK8, VNRA, VTNR / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P06756
#3: Protein Integrin beta-8


Mass: 71270.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB8 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: P26012

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Sugars , 3 types, 8 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 6 molecules

#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestN
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
1L-TGF-b3/avb8 complexCOMPLEX#1-#30MULTIPLE SOURCES
2avb8 complexCOMPLEX#2-#31RECOMBINANT
3L-TGF-b3COMPLEX#11RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.3 MDaNO
210.2 MDaNO
310.1 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Cricetulus griseus (Chinese hamster)10029
23Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 70 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 382107 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0036569
ELECTRON MICROSCOPYf_angle_d0.6198892
ELECTRON MICROSCOPYf_dihedral_angle_d5.767979
ELECTRON MICROSCOPYf_chiral_restr0.0451008
ELECTRON MICROSCOPYf_plane_restr0.0041148

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