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- PDB-8vsb: L-TGF-b3/GARP -

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Basic information

Entry
Database: PDB / ID: 8vsb
TitleL-TGF-b3/GARP
Components
  • Transforming growth factor beta activator LRRC32
  • Transforming growth factor beta-3 proprotein
KeywordsSIGNALING PROTEIN / TGFb / Complex
Function / homology
Function and homology information


establishment of protein localization to extracellular region / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / type III transforming growth factor beta receptor binding / negative regulation of macrophage cytokine production / secondary palate development / positive regulation of tight junction disassembly / response to laminar fluid shear stress ...establishment of protein localization to extracellular region / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / type III transforming growth factor beta receptor binding / negative regulation of macrophage cytokine production / secondary palate development / positive regulation of tight junction disassembly / response to laminar fluid shear stress / type II transforming growth factor beta receptor binding / type I transforming growth factor beta receptor binding / receptor ligand inhibitor activity / mammary gland development / cell-cell junction organization / transforming growth factor beta binding / digestive tract development / face morphogenesis / odontogenesis / positive regulation of filopodium assembly / negative regulation of cytokine production / Molecules associated with elastic fibres / lung alveolus development / negative regulation of activated T cell proliferation / negative regulation of vascular associated smooth muscle cell proliferation / inner ear development / TGF-beta receptor signaling activates SMADs / positive regulation of cell division / positive regulation of collagen biosynthetic process / positive regulation of SMAD protein signal transduction / ECM proteoglycans / salivary gland morphogenesis / positive regulation of epithelial to mesenchymal transition / positive regulation of stress fiber assembly / T-tubule / extracellular matrix / transforming growth factor beta receptor signaling pathway / platelet alpha granule lumen / response to progesterone / cytokine activity / female pregnancy / positive regulation of protein secretion / growth factor activity / negative regulation of transforming growth factor beta receptor signaling pathway / response to estrogen / Platelet degranulation / regulation of cell population proliferation / : / negative regulation of neuron apoptotic process / in utero embryonic development / response to hypoxia / positive regulation of MAPK cascade / positive regulation of apoptotic process / negative regulation of cell population proliferation / neuronal cell body / intracellular membrane-bounded organelle / positive regulation of cell population proliferation / positive regulation of gene expression / protein-containing complex binding / positive regulation of DNA-templated transcription / cell surface / positive regulation of transcription by RNA polymerase II / extracellular space / extracellular region / nucleoplasm / identical protein binding / plasma membrane
Similarity search - Function
Transforming growth factor beta-3 / Transforming growth factor-beta / Leucine rich repeat N-terminal 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 / Leucine-rich repeat N-terminal domain ...Transforming growth factor beta-3 / Transforming growth factor-beta / Leucine rich repeat N-terminal 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 / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / Leucine rich repeat, ribonuclease inhibitor type / Leucine-rich repeats, bacterial type / Cystine-knot cytokine / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Transforming growth factor beta-3 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.93 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 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update
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

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Assembly

Deposited unit
A: Transforming growth factor beta-3 proprotein
B: Transforming growth factor beta-3 proprotein
I: Transforming growth factor beta activator LRRC32


Theoretical massNumber of molelcules
Total (without water)155,7723
Polymers155,7723
Non-polymers00
Water00
1


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

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Components

#1: Protein Transforming growth factor beta-3 proprotein


Mass: 44858.094 Da / Num. of mol.: 2
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 Transforming growth factor beta activator LRRC32 / Garpin / Glycoprotein A repetitions predominant / GARP / Leucine-rich repeat-containing protein 32


Mass: 66056.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRC32, D11S833E / Production host: Homo sapiens (human) / References: UniProt: Q14392
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

ComponentName: L-TGF-b3/GARP complex / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
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: 2200 nm / Nominal defocus min: 1100 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151804 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0097820
ELECTRON MICROSCOPYf_angle_d0.90710635
ELECTRON MICROSCOPYf_dihedral_angle_d6.4251113
ELECTRON MICROSCOPYf_chiral_restr0.0521275
ELECTRON MICROSCOPYf_plane_restr0.0061346

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