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- EMDB-43493: L-TGF-b1/GARP -

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Basic information

Entry
Database: EMDB / ID: EMD-43493
TitleL-TGF-b1/GARP
Map dataL-TGF-b1/GARP
Sample
  • Complex: L-TGF-b1/GARP complex
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Transforming growth factor beta activator LRRC32
KeywordsTGFb / Complex / SIGNALING PROTEIN
Function / homology
Function and homology information


establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / regulation of branching involved in mammary gland duct morphogenesis ...establishment of protein localization to extracellular region / cellular response to acetaldehyde / 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 / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / regulation of branching involved in mammary gland duct morphogenesis / macrophage derived foam cell differentiation / frontal suture morphogenesis / regulation of enamel mineralization / regulation of cartilage development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / regulatory T cell differentiation / tolerance induction to self antigen / regulation of blood vessel remodeling / regulation of protein import into nucleus / embryonic liver development / extracellular matrix assembly / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / columnar/cuboidal epithelial cell maturation / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / odontoblast differentiation / positive regulation of odontogenesis / connective tissue replacement involved in inflammatory response wound healing / Langerhans cell differentiation / negative regulation of macrophage cytokine production / positive regulation of smooth muscle cell differentiation / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of exit from mitosis / secondary palate development / positive regulation of isotype switching to IgA isotypes / positive regulation of mesenchymal stem cell proliferation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / membrane protein intracellular domain proteolysis / positive regulation of receptor signaling pathway via STAT / heart valve morphogenesis / retina vasculature development in camera-type eye / TGFBR3 regulates TGF-beta signaling / mammary gland branching involved in thelarche / bronchiole development / hyaluronan catabolic process / positive regulation of vasculature development / response to laminar fluid shear stress / lens fiber cell differentiation / positive regulation of extracellular matrix assembly / negative regulation of extracellular matrix disassembly / ATP biosynthetic process / positive regulation of branching involved in ureteric bud morphogenesis / receptor catabolic process / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / type I transforming growth factor beta receptor binding / receptor ligand inhibitor activity / response to salt / germ cell migration / negative regulation of biomineral tissue development / positive regulation of mononuclear cell migration / endoderm development / phospholipid homeostasis / negative regulation of myoblast differentiation / positive regulation of chemotaxis / negative regulation of cell-cell adhesion mediated by cadherin / cell-cell junction organization / response to vitamin D / response to cholesterol / positive regulation of vascular permeability / negative regulation of interleukin-17 production / surfactant homeostasis / deubiquitinase activator activity / transforming growth factor beta binding / phosphate-containing compound metabolic process / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of chemokine (C-X-C motif) ligand 2 production / digestive tract development / positive regulation of fibroblast migration / aortic valve morphogenesis / sprouting angiogenesis / negative regulation of ossification / face morphogenesis / RUNX3 regulates CDKN1A transcription / neural tube development / positive regulation of regulatory T cell differentiation / negative regulation of cytokine production / ureteric bud development / Molecules associated with elastic fibres / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of phagocytosis / positive regulation of peptidyl-tyrosine phosphorylation / negative regulation of neuroblast proliferation / muscle cell cellular homeostasis / cellular response to insulin-like growth factor stimulus
Similarity search - Function
Transforming growth factor beta-1 proprotein / 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-1 proprotein / 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-1 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsJin M / Cheng Y / Nishimura SL
Funding support United States, 1 items
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, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43493.png

Downloads & links

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Map

FileDownload / File: emd_43493.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationL-TGF-b1/GARP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 360 pix.
= 300.24 Å		0.83 Å/pix.
x 360 pix.
= 300.24 Å		0.83 Å/pix.
x 360 pix.
= 300.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.834 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.55
Minimum - Maximum-2.4296775 - 3.990069
Average (Standard dev.)0.00020881275 (±0.05510671)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 300.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half map B of L-TGF-b1/GARP

Fileemd_43493_half_map_1.map
AnnotationHalf map B of L-TGF-b1/GARP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A of L-TGF-b1/GARP

Fileemd_43493_half_map_2.map
AnnotationHalf map A of L-TGF-b1/GARP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : L-TGF-b1/GARP complex

EntireName: L-TGF-b1/GARP complex
Components
  • Complex: L-TGF-b1/GARP complex
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Transforming growth factor beta activator LRRC32

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Supramolecule #1: L-TGF-b1/GARP complex

SupramoleculeName: L-TGF-b1/GARP complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Transforming growth factor beta-1 proprotein

MacromoleculeName: Transforming growth factor beta-1 proprotein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.399094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPPSGLRLLL LLLPLLWLLV LTPGRPAAGL STCKTIDMEL VKRKRIEAIR GQILSKLRLA SPPSQGEVPP GPLPEAVLAL YNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHNE IYDKFKQSTH SIYMFFNTSE LREAVPEPVL LSRAELRLLR L KLKVEQHV ...String:
MPPSGLRLLL LLLPLLWLLV LTPGRPAAGL STCKTIDMEL VKRKRIEAIR GQILSKLRLA SPPSQGEVPP GPLPEAVLAL YNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHNE IYDKFKQSTH SIYMFFNTSE LREAVPEPVL LSRAELRLLR L KLKVEQHV ELYQKYSNNS WRYLSNRLLA PSDSPEWLSF DVTGVVRQWL SRGGEIEGFR LSAHCSCDSR DNTLQVDING FT TGRRGDL ATIHGMNRPF LLLMATPLER AQHLQSSRHR RALDTNYCFS STEKNCCVRQ LYIDFRKDLG WKWIHEPKGY HAN FCLGPC PYIWSLDTQY SKVLALYNQH NPGASAAPCC VPQALEPLPI VYYVGRKPKV EQLSNMIVRS CKCS

UniProtKB: Transforming growth factor beta-1 proprotein

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Macromolecule #2: Transforming growth factor beta activator LRRC32

MacromoleculeName: Transforming growth factor beta activator LRRC32 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.056297 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: HQDKVPCKMV DKKVSCQVLG LLQVPSVLPP DTETLDLSGN QLRSILASPL GFYTALRHLD LSTNEISFLQ PGAFQALTHL EHLSLAHNR LAMATALSAG GLGPLPRVTS LDLSGNSLYS GLLERLLGEA PSLHTLSLAE NSLTRLTRHT FRDMPALEQL D LHSNVLMD ...String:
HQDKVPCKMV DKKVSCQVLG LLQVPSVLPP DTETLDLSGN QLRSILASPL GFYTALRHLD LSTNEISFLQ PGAFQALTHL EHLSLAHNR LAMATALSAG GLGPLPRVTS LDLSGNSLYS GLLERLLGEA PSLHTLSLAE NSLTRLTRHT FRDMPALEQL D LHSNVLMD IEDGAFEGLP RLTHLNLSRN SLTCISDFSL QQLRVLDLSC NSIEAFQTAS QPQAEFQLTW LDLRENKLLH FP DLAALPR LIYLNLSNNL IRLPTGPPQD SKGIHAPSEG WSALPLSAPS GNASGRPLSQ LLNLDLSYNE IELIPDSFLE HLT SLCFLN LSRNCLRTFE ARRLGSLPCL MLLDLSHNAL ETLELGARAL GSLRTLLLQG NALRDLPPYT FANLASLQRL NLQG NRVSP CGGPDEPGPS GCVAFSGITS LRSLSLVDNE IELLRAGAFL HTPLTELDLS SNPGLEVATG ALGGLEASLE VLALQ GNGL MVLQVDLPCF ICLKRLNLAE NRLSHLPAWT QAVSLEVLDL RNNSFSLLPG SAMGGLETSL RRLYLQGNPL SCCGNG WLA AQLHQGRVDV DATQDLICRF SSQEEVSLSH VRPEDCEKGG LKNIN

UniProtKB: Transforming growth factor beta activator LRRC32

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.1 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 318954
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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