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- EMDB-43495: avb8/L-TGF-b1/GARP focused on avb8 -

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Basic information

Entry
Database: EMDB / ID: EMD-43495
Titleavb8/L-TGF-b1/GARP focused on avb8
Map dataavb8/L-TGF-b1/GARP focused on avb8
Sample
  • Complex: avb8/L-TGF-b1/GARP complex
    • Complex: avb8 complex
    • Complex: L-TGF-b1/GARP complex
KeywordsIntegrin / Complex / SIGNALING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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 13, 2024-
Current statusNov 13, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43495.png

Downloads & links

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Map

FileDownload / File: emd_43495.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationavb8/L-TGF-b1/GARP focused on avb8
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.17 Å/pix.
x 512 pix.
= 601.19 Å		1.17 Å/pix.
x 512 pix.
= 601.19 Å		1.17 Å/pix.
x 512 pix.
= 601.19 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1742 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.4
Minimum - Maximum-1.5601149 - 2.3524742
Average (Standard dev.)-0.00023586022 (±0.047910802)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 601.1904 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B of avb8/L-TGF-b1/GARP focused on avb8

Fileemd_43495_half_map_1.map
Annotationhalf map B of avb8/L-TGF-b1/GARP focused on avb8
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A of avb8/L-TGF-b1/GARP focused on avb8

Fileemd_43495_half_map_2.map
Annotationhalf map A of avb8/L-TGF-b1/GARP focused on avb8
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : avb8/L-TGF-b1/GARP complex

EntireName: avb8/L-TGF-b1/GARP complex
Components
  • Complex: avb8/L-TGF-b1/GARP complex
    • Complex: avb8 complex
    • Complex: L-TGF-b1/GARP complex

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Supramolecule #1: avb8/L-TGF-b1/GARP complex

SupramoleculeName: avb8/L-TGF-b1/GARP complex / type: complex / ID: 1 / Parent: 0 / Details: mixture of avb8 and L-TGF-b1/GARP
Molecular weightTheoretical: 180 KDa

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Supramolecule #2: avb8 complex

SupramoleculeName: avb8 complex / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: L-TGF-b1/GARP complex

SupramoleculeName: L-TGF-b1/GARP complex / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Homo sapiens (human)

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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: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 46771
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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