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- EMDB-20797: Integrin alpha-v beta-8 in complex with latent TGF-beta, Conforma... -

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Basic information

Entry
Database: EMDB / ID: EMD-20797
TitleIntegrin alpha-v beta-8 in complex with latent TGF-beta, Conformation i (Primary map: sharpened. Additional map: unsharpened.)
Map dataIntegrin alpha-v beta-8 in complex with latent TGF-beta, Conformation i, sharpened map
Sample
  • Complex: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)
    • Complex: alpha-v beta-8 integrin
    • Complex: Transforming Growth Factor Beta-1 proprotein
Biological speciesHomo sapiens (human) / Sus scrofa (pig)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsCampbell MG / Cormier A / Cheng Y / Nishimura SL
Funding support United States, 7 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood InstituteU54HL119893 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteR01HL134183 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteR01HL113032 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteS10OD020054 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteR01GM098672 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteP41CA196276 United States
National Institutes of Health/National Heart, Lung, and Blood InstituteS10OD021741 United States
CitationJournal: Cell / Year: 2020
Title: Cryo-EM Reveals Integrin-Mediated TGF-β Activation without Release from Latent TGF-β.
Authors: Melody G Campbell / Anthony Cormier / Saburo Ito / Robert I Seed / Andrew J Bondesson / Jianlong Lou / James D Marks / Jody L Baron / Yifan Cheng / Stephen L Nishimura /
Abstract: Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. ...Integrin αvβ8 binds with exquisite specificity to latent transforming growth factor-β (L-TGF-β). This binding is essential for activating L-TGF-β presented by a variety of cell types. Inhibiting αvβ8-mediated TGF-β activation blocks immunosuppressive regulatory T cell differentiation, which is a potential therapeutic strategy in cancer. Using cryo-electron microscopy, structure-guided mutagenesis, and cell-based assays, we reveal the binding interactions between the entire αvβ8 ectodomain and its intact natural ligand, L-TGF-β, as well as two different inhibitory antibody fragments to understand the structural underpinnings of αvβ8 binding specificity and TGF-β activation. Our studies reveal a mechanism of TGF-β activation where mature TGF-β signals within the confines of L-TGF-β and the release and diffusion of TGF-β are not required. The structural details of this mechanism provide a rational basis for therapeutic strategies to inhibit αvβ8-mediated L-TGF-β activation.
History
DepositionOct 2, 2019-
Header (metadata) releaseNov 6, 2019-
Map releaseFeb 5, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.5
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.5
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_20797.png

Downloads & links

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Map

FileDownload / File: emd_20797.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationIntegrin alpha-v beta-8 in complex with latent TGF-beta, Conformation i, sharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.35 Å/pix.
x 300 pix.
= 403.5 Å		1.35 Å/pix.
x 300 pix.
= 403.5 Å		1.35 Å/pix.
x 300 pix.
= 403.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.345 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.5 / Movie #1: 0.5
Minimum - Maximum-2.598976 - 8.838453
Average (Standard dev.)0.0030261052 (±0.0663127)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 403.5 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.3451.3451.345
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z403.500403.500403.500
α/β/γ90.00090.00090.000
start NX/NY/NZ79740
NX/NY/NZ93103213
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-2.5998.8380.003

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Supplemental data

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Additional map: Integrin alpha-v beta-8 in complex with latent TGF-beta,...

Fileemd_20797_additional.map
AnnotationIntegrin alpha-v beta-8 in complex with latent TGF-beta, Conformation i (Additional unsharpened map.)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Integrin alpha-v beta-8 in complex with latent TGF-beta,...

Fileemd_20797_additional_1.map
AnnotationIntegrin alpha-v beta-8 in complex with latent TGF-beta, Conformation i (Additional unsharpened map.)
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 ...

EntireName: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)
Components
  • Complex: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)
    • Complex: alpha-v beta-8 integrin
    • Complex: Transforming Growth Factor Beta-1 proprotein

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Supramolecule #1: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 ...

SupramoleculeName: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)
type: complex / ID: 1 / Parent: 0
Molecular weightTheoretical: 260 KDa

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Supramolecule #2: alpha-v beta-8 integrin

SupramoleculeName: alpha-v beta-8 integrin / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)

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Supramolecule #3: Transforming Growth Factor Beta-1 proprotein

SupramoleculeName: Transforming Growth Factor Beta-1 proprotein / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Sus scrofa (pig)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293A

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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: 7.5
GridSupport film - Material: GRAPHENE OXIDE / Details: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 32465
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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