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- PDB-8vsc: L-TGF-b1/GARP -

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Basic information

Entry
Database: PDB / ID: 8vsc
TitleL-TGF-b1/GARP
Components
  • Transforming growth factor beta activator LRRC32
  • Transforming growth factor beta-1 proprotein
KeywordsSIGNALING PROTEIN / TGFb / Complex
Function / homology
Function and homology information


establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / columnar/cuboidal epithelial cell maturation ...establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / columnar/cuboidal epithelial cell maturation / negative regulation of skeletal muscle tissue development / macrophage derived foam cell differentiation / response to laminar fluid shear stress / embryonic liver development / regulation of enamel mineralization / regulation of branching involved in mammary gland duct morphogenesis / regulation of cartilage development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / regulation of blood vessel remodeling / regulation of protein import into nucleus / regulatory T cell differentiation / tolerance induction to self antigen / extracellular matrix assembly / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / myofibroblast differentiation / positive regulation of cardiac muscle cell differentiation / positive regulation of odontogenesis / connective tissue replacement involved in inflammatory response wound healing / Langerhans cell differentiation / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of smooth muscle cell differentiation / positive regulation of exit from mitosis / secondary palate development / negative regulation of macrophage cytokine production / odontoblast differentiation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / positive regulation of isotype switching to IgA isotypes / 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 / retina vasculature development in camera-type eye / heart valve morphogenesis / bronchiole development / mammary gland branching involved in thelarche / hyaluronan catabolic process / TGFBR3 regulates TGF-beta signaling / positive regulation of vasculature development / lens fiber cell differentiation / ATP biosynthetic process / negative regulation of extracellular matrix disassembly / type II transforming growth factor beta receptor binding / receptor catabolic process / positive regulation of branching involved in ureteric bud morphogenesis / TGFBR1 LBD Mutants in Cancer / receptor ligand inhibitor activity / positive regulation of chemotaxis / type I transforming growth factor beta receptor binding / response to salt / germ cell migration / positive regulation of mononuclear cell migration / endoderm development / negative regulation of biomineral tissue development / phospholipid homeostasis / negative regulation of cell-cell adhesion mediated by cadherin / negative regulation of myoblast differentiation / positive regulation of vascular permeability / response to cholesterol / oligodendrocyte development / cell-cell junction organization / negative regulation of interleukin-17 production / phosphate-containing compound metabolic process / surfactant homeostasis / transforming growth factor beta binding / deubiquitinase activator activity / sprouting angiogenesis / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of chemokine (C-X-C motif) ligand 2 production / negative regulation of ossification / digestive tract development / aortic valve morphogenesis / RUNX3 regulates CDKN1A transcription / response to vitamin D / face morphogenesis / positive regulation of fibroblast migration / ureteric bud development / neural tube development / positive regulation of regulatory T cell differentiation / positive regulation of peptidyl-tyrosine phosphorylation / Molecules associated with elastic fibres / negative regulation of phagocytosis / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of neuroblast proliferation / negative regulation of cytokine production / lung alveolus development / Syndecan interactions
Similarity search - Function
Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / TGF-beta, propeptide / TGF-beta propeptide / Leucine rich repeat N-terminal 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-1 proprotein / Transforming growth factor-beta / TGF-beta, propeptide / TGF-beta propeptide / Leucine rich repeat N-terminal 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. / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / 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-1 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 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 16, 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

Downloads & links

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Assembly

Deposited unit
A: Transforming growth factor beta-1 proprotein
B: Transforming growth factor beta-1 proprotein
I: Transforming growth factor beta activator LRRC32


Theoretical massNumber of molelcules
Total (without water)154,8543
Polymers154,8543
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-1 proprotein


Mass: 44399.094 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB1, TGFB / Production host: Homo sapiens (human) / References: UniProt: P01137
#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-b1/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: 46 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: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 318954 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039026
ELECTRON MICROSCOPYf_angle_d0.68312258
ELECTRON MICROSCOPYf_dihedral_angle_d5.6671229
ELECTRON MICROSCOPYf_chiral_restr0.0411405
ELECTRON MICROSCOPYf_plane_restr0.0061582

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