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- EMDB-43492: L-TGF-b3/GARP -

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Basic information

Entry
Database: EMDB / ID: EMD-43492
TitleL-TGF-b3/GARP
Map dataL-TGF-b3/GARP
Sample
  • Complex: L-TGF-b3/GARP complex
    • Protein or peptide: Transforming growth factor beta-3 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 / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / receptor ligand inhibitor activity / type III transforming growth factor beta receptor binding / positive regulation of tight junction disassembly / negative regulation of macrophage cytokine production / secondary palate development ...establishment of protein localization to extracellular region / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / receptor ligand inhibitor activity / type III transforming growth factor beta receptor binding / positive regulation of tight junction disassembly / negative regulation of macrophage cytokine production / secondary palate development / response to laminar fluid shear stress / type II transforming growth factor beta receptor binding / type I transforming growth factor beta receptor binding / mammary gland development / digestive tract development / cell-cell junction organization / transforming growth factor beta binding / face morphogenesis / odontogenesis / Molecules associated with elastic fibres / positive regulation of filopodium assembly / negative regulation of cytokine production / lung alveolus development / negative regulation of activated T cell proliferation / TGF-beta receptor signaling activates SMADs / negative regulation of vascular associated smooth muscle cell proliferation / positive regulation of SMAD protein signal transduction / inner ear development / positive regulation of cell division / ECM proteoglycans / positive regulation of collagen biosynthetic process / 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 / cytokine activity / response to progesterone / female pregnancy / positive regulation of protein secretion / negative regulation of transforming growth factor beta receptor signaling pathway / growth factor activity / response to estrogen / Platelet degranulation / regulation of cell population proliferation / collagen-containing extracellular matrix / in utero embryonic development / negative regulation of neuron apoptotic process / positive regulation of MAPK cascade / response to hypoxia / positive regulation of apoptotic process / negative regulation of cell population proliferation / external side of plasma membrane / intracellular membrane-bounded organelle / neuronal cell body / positive regulation of cell population proliferation / protein-containing complex binding / positive regulation of gene expression / 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 / 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 / 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-3 proprotein / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.93 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_43492.png

Downloads & links

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Map

FileDownload / File: emd_43492.map.gz / Format: CCP4 / Size: 347.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationL-TGF-b3/GARP
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 450 pix.
= 298.8 Å		0.66 Å/pix.
x 450 pix.
= 298.8 Å		0.66 Å/pix.
x 450 pix.
= 298.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.664 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-2.175897 - 3.3083508
Average (Standard dev.)-0.0001411571 (±0.046085704)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions450450450
Spacing450450450
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B of L-TGF-b3/GARP

Fileemd_43492_half_map_1.map
Annotationhalf map B of L-TGF-b3/GARP
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map B of L-TGF-b3/GARP

Fileemd_43492_half_map_2.map
Annotationhalf map B of L-TGF-b3/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-b3/GARP complex

EntireName: L-TGF-b3/GARP complex
Components
  • Complex: L-TGF-b3/GARP complex
    • Protein or peptide: Transforming growth factor beta-3 proprotein
    • Protein or peptide: Transforming growth factor beta activator LRRC32

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Supramolecule #1: L-TGF-b3/GARP complex

SupramoleculeName: L-TGF-b3/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-3 proprotein

MacromoleculeName: Transforming growth factor beta-3 proprotein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.858094 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LSTCTTLDFG HIKKKRVEAI RGQILSKLRL TSPPEPTVMT HVPYQVLALY NSTRELLEEM HGEREEGCTQ ENTESEYYAK EIHKFDMIQ GLAEHNELAV CPKGITSKVF RFNVSSVEKN RTNLFRAEFR VLRVPNPSSK RNEQRIELFQ ILRPDEHIAK Q RYIGGKNL ...String:
LSTCTTLDFG HIKKKRVEAI RGQILSKLRL TSPPEPTVMT HVPYQVLALY NSTRELLEEM HGEREEGCTQ ENTESEYYAK EIHKFDMIQ GLAEHNELAV CPKGITSKVF RFNVSSVEKN RTNLFRAEFR VLRVPNPSSK RNEQRIELFQ ILRPDEHIAK Q RYIGGKNL PTRGTAEWLS FDVTDTVREW LLRRESNLGL EISIHCPCHT FQPNGDILEN IHEVMEIKFK GVDNEDDHGR GD LGRLKKQ KDHHNPHLIL MMIPPHRLDN PGQGGQRKKR ALDTNYCFRN LEENCCVRPL YIDFRQDLGW KWVHEPKGYY ANF CSGPCP YLRSADTTHS TVLGLYNTLN PEASASPCCV PQDLEPLTIL YYVGRTPKVE QLSNMVVKSC KCS

UniProtKB: Transforming growth factor beta-3 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: 47.0 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: 2.93 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 151804
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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