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- EMDB-43489: L-TGF-b3/avb8 -

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Basic information

Entry
Database: EMDB / ID: EMD-43489
TitleL-TGF-b3/avb8
Map dataL-TGF-b3/avb8 complex
Sample
  • Complex: L-TGF-b3/avb8 complex
    • Complex: avb8 complex
      • Protein or peptide: Integrin alpha-V
      • Protein or peptide: Integrin beta-8
    • Complex: L-TGF-b3
      • Protein or peptide: Transforming growth factor beta-3 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MAGNESIUM ION
KeywordsTGFb / Complex / SIGNALING PROTEIN
Function / homology
Function and homology information


ganglioside metabolic process / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / type III transforming growth factor beta receptor binding / positive regulation of tight junction disassembly / Langerhans cell differentiation / negative regulation of macrophage cytokine production / integrin alphav-beta8 complex ...ganglioside metabolic process / uterine wall breakdown / detection of hypoxia / frontal suture morphogenesis / embryonic neurocranium morphogenesis / type III transforming growth factor beta receptor binding / positive regulation of tight junction disassembly / Langerhans cell differentiation / negative regulation of macrophage cytokine production / integrin alphav-beta8 complex / integrin alphav-beta6 complex / hard palate development / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / secondary palate development / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / response to laminar fluid shear stress / extracellular matrix protein binding / Laminin interactions / placenta blood vessel development / type II transforming growth factor beta receptor binding / negative regulation of lipoprotein metabolic process / integrin alphav-beta3 complex / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / type I transforming growth factor beta receptor binding / alphav-beta3 integrin-HMGB1 complex / mammary gland development / negative regulation of lipid transport / cell-cell junction organization / regulation of phagocytosis / negative regulation of low-density lipoprotein receptor activity / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / digestive tract development / positive regulation of small GTPase mediated signal transduction / filopodium membrane / extracellular matrix binding / apolipoprotein A-I-mediated signaling pathway / cartilage development / apoptotic cell clearance / wound healing, spreading of epidermal cells / face morphogenesis / integrin complex / heterotypic cell-cell adhesion / odontogenesis / positive regulation of filopodium assembly / Molecules associated with elastic fibres / positive regulation of intracellular signal transduction / cell adhesion mediated by integrin / microvillus membrane / negative chemotaxis / Syndecan interactions / lung alveolus development / cell-substrate adhesion / endodermal cell differentiation / positive regulation of osteoblast proliferation / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / negative regulation of vascular associated smooth muscle cell proliferation / positive regulation of SMAD protein signal transduction / inner ear development / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / positive regulation of cell division / fibronectin binding / negative regulation of lipid storage / positive regulation of collagen biosynthetic process / ECM proteoglycans / vasculogenesis / Integrin cell surface interactions / voltage-gated calcium channel activity / salivary gland morphogenesis / specific granule membrane / coreceptor activity / phagocytic vesicle / positive regulation of epithelial to mesenchymal transition / extrinsic apoptotic signaling pathway in absence of ligand / positive regulation of stress fiber assembly / T-tubule / ERK1 and ERK2 cascade / positive regulation of cell adhesion / substrate adhesion-dependent cell spreading / transforming growth factor beta receptor signaling pathway / cell-matrix adhesion / platelet alpha granule lumen / Signal transduction by L1 / cytokine activity / response to progesterone / integrin-mediated signaling pathway / female pregnancy / positive regulation of protein secretion / negative regulation of extrinsic apoptotic signaling pathway / protein kinase C binding / negative regulation of transforming growth factor beta receptor signaling pathway / calcium ion transmembrane transport
Similarity search - Function
Transforming growth factor beta-3 / Transforming growth factor-beta / 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 / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain ...Transforming growth factor beta-3 / Transforming growth factor-beta / 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 / Transforming growth factor-beta, C-terminal / Transforming growth factor beta like domain / TGF-beta family profile. / : / Integrin alpha Ig-like domain 3 / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain cysteine-rich domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha cytoplasmic region / EGF-like domain, extracellular / EGF-like domain / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / Integrin alpha chain / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / : / Integrin alpha Ig-like domain 2 / Integrins alpha chain signature. / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin domain superfamily / Integrin alpha, N-terminal / Cystine-knot cytokine / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain
Similarity search - Domain/homology
Integrin alpha-V / Transforming growth factor beta-3 proprotein / Integrin beta-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.73 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_43489.png

Downloads & links

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Map

FileDownload / File: emd_43489.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationL-TGF-b3/avb8 complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.35 Å/pix.
x 360 pix.
= 484.2 Å		1.35 Å/pix.
x 360 pix.
= 484.2 Å		1.35 Å/pix.
x 360 pix.
= 484.2 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: 1.2
Minimum - Maximum-7.4995613 - 9.608758
Average (Standard dev.)-0.000086335145 (±0.09742382)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 484.2 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/avb8 complex

Fileemd_43489_half_map_1.map
Annotationhalf map B of L-TGF-b3/avb8 complex
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-b3/avb8 complex

Fileemd_43489_half_map_2.map
Annotationhalf map A of L-TGF-b3/avb8 complex
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/avb8 complex

EntireName: L-TGF-b3/avb8 complex
Components
  • Complex: L-TGF-b3/avb8 complex
    • Complex: avb8 complex
      • Protein or peptide: Integrin alpha-V
      • Protein or peptide: Integrin beta-8
    • Complex: L-TGF-b3
      • Protein or peptide: Transforming growth factor beta-3 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MAGNESIUM ION

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Supramolecule #1: L-TGF-b3/avb8 complex

SupramoleculeName: L-TGF-b3/avb8 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Molecular weightTheoretical: 100 KDa

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Supramolecule #2: avb8 complex

SupramoleculeName: avb8 complex / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2-#3
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: L-TGF-b3

SupramoleculeName: L-TGF-b3 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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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: 1 / 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: Integrin alpha-V

MacromoleculeName: Integrin alpha-V / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106.375805 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR ...String:
FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKCD WSSTRRCQPI EFDATGNRDY AKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF LQDGTKTVEY APCRSQDIDA DGQGFCQGGF S IDFTKADR VLLGGPGSFY WQGQLISDQV AEIVSKYDPN VYSIKYNNQL ATRTAQAIFD DSYLGYSVAV GDFNGDGIDD FV SGVPRAA RTLGMVYIYD GKNMSSLYNF TGEQMAAYFG FSVAATDING DDYADVFIGA PLFMDRGSDG KLQEVGQVSV SLQ RASGDF QTTKLNGFEV FARFGSAIAP LGDLDQDGFN DIAIAAPYGG EDKKGIVYIF NGRSTGLNAV PSQILEGQWA ARSM PPSFG YSMKGATDID KNGYPDLIVG AFGVDRAILY RARPVITVNA GLEVYPSILN QDNKTCSLPG TALKVSCFNV RFCLK ADGK GVLPRKLNFQ VELLLDKLKQ KGAIRRALFL YSRSPSHSKN MTISRGGLMQ CEELIAYLRD ESEFRDKLTP ITIFME YRL DYRTAADTTG LQPILNQFTP ANISRQAHIL LDCGEDNVCK PKLEVSVDSD QKKIYIGDDN PLTLIVKAQN QGEGAYE AE LIVSIPLQAD FIGVVRNNEA LARLSCAFKT ENQTRQVVCD LGNPMKAGTQ LLAGLRFSVH QQSEMDTSVK FDLQIQSS N LFDKVSPVVS HKVDLAVLAA VEIRGVSSPD HVFLPIPNWE HKENPETEED VGPVVQHIYE LRNNGPSSFS KAMLHLQWP YKYNNNTLLY ILHYDIDGPM NCTSDMEINP LRIKISSLQT TEKNDTVAGQ GERDHLITKR DLALSEGDIH TLGCGVAQCL KIVCQVGRL DRGKSAILYV KSLLWTETFM NKENQNHSYS LKSSASFNVI EFPYKNLPIE DITNSTLVTT NVTWGIQPAP M PV

UniProtKB: Integrin alpha-V

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Macromolecule #3: Integrin beta-8

MacromoleculeName: Integrin beta-8 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 71.270758 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: EDNRCASSNA ASCARCLALG PECGWCVQED FISGGSRSER CDIVSNLISK GCSVDSIEYP SVHVIIPTEN EINTQVTPGE VSIQLRPGA EANFMLKVHP LKKYPVDLYY LVDVSASMHN NIEKLNSVGN DLSRKMAFFS RDFRLGFGSY VDKTVSPYIS I HPERIHNQ ...String:
EDNRCASSNA ASCARCLALG PECGWCVQED FISGGSRSER CDIVSNLISK GCSVDSIEYP SVHVIIPTEN EINTQVTPGE VSIQLRPGA EANFMLKVHP LKKYPVDLYY LVDVSASMHN NIEKLNSVGN DLSRKMAFFS RDFRLGFGSY VDKTVSPYIS I HPERIHNQ CSDYNLDCMP PHGYIHVLSL TENITEFEKA VHRQKISGNI DTPEGGFDAM LQAAVCESHI GWRKEAKRLL LV MTDQTSH LALDSKLAGI VVPNDGNCHL KNNVYVKSTT MEHPSLGQLS EKLIDNNINV IFAVQGKQFH WYKDLLPLLP GTI AGEIES KAANLNNLVV EAYQKLISEV KVQVENQVQG IYFNITAICP DGSRKPGMEG CRNVTSNDEV LFNVTVTMKK CDVT GGKNY AIIKPIGFNE TAKIHIHRNC SCQCEDNRGP KGKCVDETFL DSKCFQCDEN KCHFDEDQFS SESCKSHKDQ PVCSG RGVC VCGKCSCHKI KLGKVYGKYC EKDDFSCPYH HGNLCAGHGE CEAGRCQCFS GWEGDRCQCP SAAAQHCVNS KGQVCS GRG TCVCGRCECT DPRSIGRFCE HCPTCYTACK ENWNCMQCLH PHNLSQAILD QCKTSCALME QQHYVDQTSE CFSSPSY LR

UniProtKB: Integrin beta-8

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 5 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #8: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 8 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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 K2 SUMMIT (4k x 4k) / 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 / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 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: 2.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 382107
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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