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- EMDB-43494: avb8/L-TGF-b1/GARP -

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Basic information

Entry
Database: EMDB / ID: EMD-43494
Titleavb8/L-TGF-b1/GARP
Map dataL-TGF-b1/GARP/avb8
Sample
  • Complex: avb8/L-TGF-b1/GARP complex
    • Complex: avb8 complex
      • Protein or peptide: Integrin alpha-V heavy chain
      • Protein or peptide: Integrin beta-8
    • Complex: L-TGF-b1/GARP complex
      • Protein or peptide: Transforming growth factor beta activator LRRC32
      • Protein or peptide: Transforming growth factor beta-1 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MAGNESIUM ION
KeywordsIntegrin / Complex / SIGNALING PROTEIN
Function / homology
Function and homology information


establishment of protein localization to extracellular region / ganglioside metabolic process / Langerhans cell differentiation / secondary palate development / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding ...establishment of protein localization to extracellular region / ganglioside metabolic process / Langerhans cell differentiation / secondary palate development / integrin alphav-beta8 complex / integrin alphav-beta6 complex / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / placenta blood vessel development / Laminin interactions / receptor ligand inhibitor activity / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / alphav-beta3 integrin-HMGB1 complex / negative regulation of lipid transport / hard palate development / regulation of phagocytosis / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / positive regulation of small GTPase mediated signal transduction / cartilage development / filopodium membrane / extracellular matrix binding / negative regulation of low-density lipoprotein particle clearance / apolipoprotein A-I-mediated signaling pathway / apoptotic cell clearance / wound healing, spreading of epidermal cells / integrin complex / heterotypic cell-cell adhesion / Molecules associated with elastic fibres / negative regulation of cytokine production / negative chemotaxis / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Syndecan interactions / cell adhesion mediated by integrin / positive regulation of osteoblast proliferation / microvillus membrane / cell-substrate adhesion / negative regulation of activated T cell proliferation / endodermal cell differentiation / PECAM1 interactions / TGF-beta receptor signaling activates SMADs / positive regulation of intracellular signal transduction / fibronectin binding / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / ECM proteoglycans / Integrin cell surface interactions / vasculogenesis / voltage-gated calcium channel activity / specific granule membrane / coreceptor activity / phagocytic vesicle / ERK1 and ERK2 cascade / extrinsic apoptotic signaling pathway in absence of ligand / extracellular matrix / positive regulation of cell adhesion / substrate adhesion-dependent cell spreading / transforming growth factor beta receptor signaling pathway / protein kinase C binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / cell-matrix adhesion / Signal transduction by L1 / integrin-mediated signaling pathway / negative regulation of extrinsic apoptotic signaling pathway / negative regulation of transforming growth factor beta receptor signaling pathway / cell-cell adhesion / calcium ion transmembrane transport / VEGFA-VEGFR2 Pathway / response to virus / ruffle membrane / integrin binding / positive regulation of angiogenesis / cell migration / positive regulation of cytosolic calcium ion concentration / virus receptor activity / protease binding / angiogenesis / cell adhesion / immune response / positive regulation of cell migration / negative regulation of gene expression / external side of plasma membrane / focal adhesion / positive regulation of cell population proliferation / Neutrophil degranulation / positive regulation of gene expression / symbiont entry into host cell / cell surface / extracellular space / extracellular exosome
Similarity search - Function
Teneurin-like EGF domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine rich repeat, ribonuclease inhibitor type / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin alpha cytoplasmic region / Integrins beta chain EGF (I-EGF) domain profile. ...Teneurin-like EGF domain / Leucine rich repeat N-terminal domain / Leucine-rich repeat N-terminal domain / Leucine rich repeat N-terminal domain / Leucine rich repeat, ribonuclease inhibitor type / : / Integrin alpha Ig-like domain 3 / Integrin EGF domain / Integrin alpha cytoplasmic region / Integrins beta chain EGF (I-EGF) domain profile. / Integrin beta subunit, VWA domain / Integrin beta subunit / Integrin beta N-terminal / Integrin beta chain VWA domain / Integrin plexin domain / Integrins beta chain EGF (I-EGF) domain signature. / Integrin beta subunits (N-terminal portion of extracellular region) / Integrin alpha-2 / Integrin alpha Ig-like domain 1 / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / Integrin alpha chain / Integrin alpha beta-propellor / : / Integrin alpha Ig-like domain 2 / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin alpha, N-terminal / Integrin domain superfamily / Leucine-rich repeats, bacterial type / PSI domain / domain found in Plexins, Semaphorins and Integrins / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / EGF-like domain / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Integrin alpha-V / Integrin beta-8 / Transforming growth factor beta activator LRRC32
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 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 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43494.png

Downloads & links

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Map

FileDownload / File: emd_43494.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationL-TGF-b1/GARP/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-1.4487923 - 2.5538673
Average (Standard dev.)-0.00048373707 (±0.058661763)
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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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
      • Protein or peptide: Integrin alpha-V heavy chain
      • Protein or peptide: Integrin beta-8
    • Complex: L-TGF-b1/GARP complex
      • Protein or peptide: Transforming growth factor beta activator LRRC32
      • Protein or peptide: Transforming growth factor beta-1 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MAGNESIUM ION

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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 / Macromolecule list: #1-#4 / Details: mixture of avb8 and L-TGF-b1/GARP
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 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-b1/GARP complex

SupramoleculeName: L-TGF-b1/GARP complex / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1, #4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transforming growth factor beta activator LRRC32

MacromoleculeName: Transforming growth factor beta activator LRRC32 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.344055 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CKMVDKKVSC QVLGLLQVPS VLPPDTETLD LSGNQLRSIL ASPLGFYTAL RHLDLSTNEI SFLQPGAFQA LTHLEHLSLA HNRLAMATA LSAGGLGPLP RVTSLDLSGN SLYSGLLERL LGEAPSLHTL SLAENSLTRL TRHTFRDMPA LEQLDLHSNV L MDIEDGAF ...String:
CKMVDKKVSC QVLGLLQVPS VLPPDTETLD LSGNQLRSIL ASPLGFYTAL RHLDLSTNEI SFLQPGAFQA LTHLEHLSLA HNRLAMATA LSAGGLGPLP RVTSLDLSGN SLYSGLLERL LGEAPSLHTL SLAENSLTRL TRHTFRDMPA LEQLDLHSNV L MDIEDGAF EGLPRLTHLN LSRNSLTCIS DFSLQQLRVL DLSCNSIEAF QTASQPQAEF QLTWLDLREN KLLHFPDLAA LP RLIYLNL SNNLIRLPTG PPQDSKGIHA PSEGWSALPL SAPSGNASGR PLSQLLNLDL SYNEIELIPD SFLEHLTSLC FLN LSRNCL RTFEARRLGS LPCLMLLDLS HNALETLELG ARALGSLRTL LLQGNALRDL PPYTFANLAS LQRLNLQGNR VSPC GGPDE PGPSGCVAFS GITSLRSLSL VDNEIELLRA GAFLHTPLTE LDLSSNPGLE VATGALGGLE ASLEVLALQG NGLMV LQVD LPCFICLKRL NLAENRLSHL PAWTQAVSLE VLDLRNNSFS LLPGSAMGGL ETSLRRLYLQ GNPLSCCGNG WLAAQL HQG RVD

UniProtKB: Transforming growth factor beta activator LRRC32

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Macromolecule #2: Integrin alpha-V heavy chain

MacromoleculeName: Integrin alpha-V heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 65.268188 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

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: 39.574234 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: INTQVTPGEV SIQLRPGAEA NFMLKVHPLK KYPVDLYYLV DVSASMHNNI EKLNSVGNDL SRKMAFFSRD FRLGFGSYVD KTVSPYISI HPERIHNQCS DYNLDCMPPH GYIHVLSLTE NITEFEKAVH RQKISGNIDT PEGGFDAMLQ AAVCESHIGW R KEAKRLLL ...String:
INTQVTPGEV SIQLRPGAEA NFMLKVHPLK KYPVDLYYLV DVSASMHNNI EKLNSVGNDL SRKMAFFSRD FRLGFGSYVD KTVSPYISI HPERIHNQCS DYNLDCMPPH GYIHVLSLTE NITEFEKAVH RQKISGNIDT PEGGFDAMLQ AAVCESHIGW R KEAKRLLL VMTDQTSHLA LDSKLAGIVV PNDGNCHLKN NVYVKSTTME HPSLGQLSEK LIDNNINVIF AVQGKQFHWY KD LLPLLPG TIAGEIESKA ANLNNLVVEA YQKLISEVKV QVENQVQGIY FNITAICPDG SRKPGMEGCR NVTSNDEVLF NVT VTMKKC DVTGGKNYAI IKPIGFNETA KIHIHRNC

UniProtKB: Integrin beta-8

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Macromolecule #4: Transforming growth factor beta-1 proprotein

MacromoleculeName: Transforming growth factor beta-1 proprotein / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.323219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: LSTCKTIDME LVKRKRIEAI RGQILSKLRL ASPPSQGEVP PGPLPEAVLA LYNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHN EIYDKFKQST HSIYMFFNTS ELREAVPEPV LLSRAELRLL RLKLKVEQHV ELYQKYSNNS WRYLSNRLLA P SDSPEWLS ...String:
LSTCKTIDME LVKRKRIEAI RGQILSKLRL ASPPSQGEVP PGPLPEAVLA LYNSTRDRVA GESAEPEPEP EADYYAKEVT RVLMVETHN EIYDKFKQST HSIYMFFNTS ELREAVPEPV LLSRAELRLL RLKLKVEQHV ELYQKYSNNS WRYLSNRLLA P SDSPEWLS FDVTGVVRQW LSRGGEIEGF RLSAHCSCDS RDNTLQVDIN GFTTGRRGDL ATIHGMNRPF LLLMATPLER AQ HLQSSRH RRALDTNYCF SSTEKNCCVR QLYIDFRKDL GWKWIHEPKG YHANFCLGPC PYIWSLDTQY SKVLALYNQH NPG ASAAPC CVPQALEPLP IVYYVGRKPK VEQLSNMIVR SCKCS

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / 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 #8: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 8 / Number of copies: 5 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #9: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 9 / 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 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: 3.2 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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