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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 / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / regulation of branching involved in mammary gland duct morphogenesis / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / embryonic liver development / negative regulation of skeletal muscle tissue development ...establishment of protein localization to extracellular region / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / regulation of branching involved in mammary gland duct morphogenesis / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / embryonic liver development / negative regulation of skeletal muscle tissue development / frontal suture morphogenesis / regulation of enamel mineralization / regulation of cartilage development / regulatory T cell differentiation / TGFBR2 MSI Frameshift Mutants in Cancer / TGFBR3 regulates TGF-beta signaling / regulation of blood vessel remodeling / tolerance induction to self antigen / regulation of striated muscle tissue development / regulation of protein import into nucleus / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / columnar/cuboidal epithelial cell maturation / receptor ligand inhibitor activity / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / myofibroblast differentiation / positive regulation of cardiac muscle cell differentiation / Langerhans cell differentiation / positive regulation of receptor signaling pathway via STAT / positive regulation of exit from mitosis / positive regulation of odontogenesis / extracellular matrix assembly / connective tissue replacement involved in inflammatory response wound healing / odontoblast differentiation / negative regulation of macrophage cytokine production / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of smooth muscle cell differentiation / positive regulation of isotype switching to IgA isotypes / positive regulation of mesenchymal stem cell proliferation / secondary palate development / mammary gland branching involved in thelarche / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / retina vasculature development in camera-type eye / membrane protein intracellular domain proteolysis / response to laminar fluid shear stress / heart valve morphogenesis / positive regulation of vasculature development / bronchiole development / hyaluronan catabolic process / germ cell migration / receptor catabolic process / ATP biosynthetic process / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of extracellular matrix assembly / lens fiber cell differentiation / negative regulation of extracellular matrix disassembly / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / negative regulation of biomineral tissue development / positive regulation of mononuclear cell migration / positive regulation of chemotaxis / phospholipid homeostasis / response to salt / type I transforming growth factor beta receptor binding / endoderm development / negative regulation of myoblast differentiation / digestive tract development / positive regulation of vascular permeability / positive regulation of endothelial cell apoptotic process / response to vitamin D / cell-cell junction organization / positive regulation of regulatory T cell differentiation / response to cholesterol / transforming growth factor beta binding / negative regulation of interleukin-17 production / surfactant homeostasis / deubiquitinase activator activity / negative regulation of release of sequestered calcium ion into cytosol / negative regulation of ossification / positive regulation of fibroblast migration / positive regulation of chemokine (C-X-C motif) ligand 2 production / phosphate-containing compound metabolic process / aortic valve morphogenesis / sprouting angiogenesis / face morphogenesis / negative regulation of phagocytosis / neural tube development / RUNX3 regulates CDKN1A transcription / Molecules associated with elastic fibres / negative regulation of cytokine production / ventricular cardiac muscle tissue morphogenesis / cellular response to insulin-like growth factor stimulus / ureteric bud development / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of neuroblast proliferation / macrophage derived foam cell differentiation / Syndecan interactions / muscle cell cellular homeostasis
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 / 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 / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Transforming growth factor-beta (TGF-beta) family / Leucine rich repeat, ribonuclease inhibitor type / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / 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-
UpdateOct 2, 2024-
Current statusOct 2, 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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