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- EMDB-20794: Integrin alpha-v beta-8 in complex with latent TGF-beta (Primary ... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-20794 | ||||||||||||||||||||||||
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Title | Integrin alpha-v beta-8 in complex with latent TGF-beta (Primary map: sharpened. Additional map: unsharpened.) | ||||||||||||||||||||||||
![]() | Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation iv (Primary map: sharpened. Additional map: unsharpened.) | ||||||||||||||||||||||||
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Function / homology | ![]() Platelet degranulation / Cell surface interactions at the vascular wall / Molecules associated with elastic fibres / TGF-beta receptor signaling activates SMADs / Syndecan interactions / RUNX3 regulates CDKN1A transcription / RUNX3 regulates p14-ARF / Downregulation of TGF-beta receptor signaling / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Regulation of RUNX3 expression and activity ...Platelet degranulation / Cell surface interactions at the vascular wall / Molecules associated with elastic fibres / TGF-beta receptor signaling activates SMADs / Syndecan interactions / RUNX3 regulates CDKN1A transcription / RUNX3 regulates p14-ARF / Downregulation of TGF-beta receptor signaling / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / Regulation of RUNX3 expression and activity / ganglioside metabolic process / regulation of binding / regulation of DNA binding / positive regulation of microglia differentiation / negative regulation of skeletal muscle tissue development / regulation of striated muscle tissue development / regulation of protein import into nucleus / type III transforming growth factor beta receptor binding / Langerhans cell differentiation / negative regulation of hyaluronan biosynthetic process / extracellular matrix assembly / integrin alphav-beta6 complex / integrin alphav-beta8 complex / hard palate development / transforming growth factor beta production / negative regulation of macrophage cytokine production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / odontoblast differentiation / : / opsonin binding / positive regulation of isotype switching to IgA isotypes / integrin alphav-beta1 complex / membrane protein intracellular domain proteolysis / Cross-presentation of particulate exogenous antigens (phagosomes) / extracellular matrix protein binding / hyaluronan catabolic process / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / Laminin interactions / receptor catabolic process / placenta blood vessel development / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / type II transforming growth factor beta receptor binding / alphav-beta3 integrin-PKCalpha complex / entry into host cell by a symbiont-containing vacuole / type I transforming growth factor beta receptor binding / alphav-beta3 integrin-HMGB1 complex / positive regulation of chemotaxis / negative regulation of lipid transport / negative regulation of myoblast differentiation / negative regulation of low-density lipoprotein receptor activity / cell-cell junction organization / regulation of phagocytosis / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / response to cholesterol / filopodium membrane / positive regulation of small GTPase mediated signal transduction / extracellular matrix binding / positive regulation of fibroblast migration / phosphate-containing compound metabolic process / apolipoprotein A-I-mediated signaling pathway / cartilage development / apoptotic cell clearance / wound healing, spreading of epidermal cells / heterotypic cell-cell adhesion / integrin complex / Molecules associated with elastic fibres / positive regulation of intracellular signal transduction / positive regulation of epidermal growth factor receptor signaling pathway / microvillus membrane / negative chemotaxis / cell adhesion mediated by integrin / Syndecan interactions / negative regulation of cell-cell adhesion / negative regulation of fat cell differentiation / cell-substrate adhesion / endodermal cell differentiation / positive regulation of interleukin-17 production / positive regulation of osteoblast proliferation / TGF-beta receptor signaling activates SMADs / PECAM1 interactions / positive regulation of SMAD protein signal transduction / lamellipodium membrane / negative regulation of macrophage derived foam cell differentiation / negative regulation of blood vessel endothelial cell migration / negative regulation of lipid storage / fibronectin binding / positive regulation of cell division / negative regulation of cell cycle / positive regulation of cell adhesion / ECM proteoglycans / positive regulation of collagen biosynthetic process / voltage-gated calcium channel activity / positive regulation of blood vessel endothelial cell migration / epithelial to mesenchymal transition / vasculogenesis Similarity search - Function | ||||||||||||||||||||||||
Biological species | ![]() ![]() ![]() | ||||||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||||||||||||||
![]() | Campbell MG / Cormier A / Cheng Y / Nishimura SL | ||||||||||||||||||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 1.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21.8 KB 21.8 KB | Display Display | ![]() |
Images | ![]() | 99.6 KB | ||
Others | ![]() | 52.1 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 298.8 KB | Display | ![]() |
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Full document | ![]() | 298.4 KB | Display | |
Data in XML | ![]() | 6.5 KB | Display | |
Data in CIF | ![]() | 7.4 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6ujaMC ![]() 6ujbC ![]() 6ujcC C: citing same article ( M: atomic model generated by this map |
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Similar structure data | |
EM raw data | ![]() Data size: 1.2 TB Data #1: Unaligned 80-frame movies of αVβ8 integrin bound to latent TGF-β on a holey carbon grid [micrographs - multiframe] Data #2: Dose-weighted aligned micrographs of αVβ8 integrin bound to latent TGF-β on a holey carbon grid [micrographs - single frame] Data #3: Dose-weighted aligned particle stacks of αVβ8 integrin bound to latent TGF-β on a holey carbon grid [picked particles - single frame - processed]) ![]() Data size: 2.2 TB Data #1: Unaligned 80-frame movies of αVβ8 integrin bound to latent TGF-β on a graphene oxide grid [micrographs - multiframe] Data #2: Dose-weighted aligned micrographs of αVβ8 integrin bound to latent TGF-β on a graphene oxide grid [micrographs - single frame] Data #3: Dose-weighted aligned particle stacks of αVβ8 integrin bound to latent TGF-β on a graphene oxide grid [picked particles - single frame - processed]) |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation iv (Primary map: sharpened. Additional map: unsharpened.) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.345 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: Integrin alpha-v beta-8 in complex with latent TGF-beta,...
File | emd_20794_additional.map | ||||||||||||
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Annotation | Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation iv (Additional unsharpened map.) | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 ...
Entire | Name: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1) |
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Components |
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-Supramolecule #1: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 ...
Supramolecule | Name: Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1) type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 |
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Molecular weight | Theoretical: 260 KDa |
-Supramolecule #2: alpha-v beta-8 integrin
Supramolecule | Name: alpha-v beta-8 integrin / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() ![]() |
-Supramolecule #3: Transforming Growth Factor Beta-1 proprotein
Supramolecule | Name: Transforming Growth Factor Beta-1 proprotein / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3 Details: LTGFb is a homodimer in the sample, but only a single chain is modeled. |
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Source (natural) | Organism: ![]() ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Integrin alpha-V
Macromolecule | Name: Integrin alpha-V / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 112.813352 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 PVPVWVII LAVLAGLLLL AVLVFVMYRM GFFKRVRPPQ EEQEREQLQP HENGEGNSET |
-Macromolecule #2: Integrin beta-8
Macromolecule | Name: Integrin beta-8 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 81.276664 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 IFFIIFIVTF LIGLLKVLII RQVILQWNSN KIKSSSDYRV SASKKDKLIL QSVCTRAVTY RREKPEEIKM DISKLNAH E TFRCNF |
-Macromolecule #3: Transforming growth factor beta-1 proprotein
Macromolecule | Name: Transforming growth factor beta-1 proprotein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 41.434449 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GPLSTCKTID MELVKRKRIE AIRGQILSKL RLASPPSQGD VPPGPLPEAV LALYNSTRDR VAGESVEPEP EPEADYYAKE VTRVLMVES GNQIYDKFKG TPHSLYMLFN TSELREAVPE PVLLSRAELR LLRLKLKVEQ HVELYQKYSN DSWRYLSNRL L APSDSPEW ...String: GPLSTCKTID MELVKRKRIE AIRGQILSKL RLASPPSQGD VPPGPLPEAV LALYNSTRDR VAGESVEPEP EPEADYYAKE VTRVLMVES GNQIYDKFKG TPHSLYMLFN TSELREAVPE PVLLSRAELR LLRLKLKVEQ HVELYQKYSN DSWRYLSNRL L APSDSPEW LSFDVTGVVR QWLTRREAIE GFRLSAHCSC DSKDNTLHVE INGFNSGRRG DLATIHGMNR PFLLLMATPL ER AQHLHSS RHRRALDTNY CFSSTEKNCC VRQLYIDFRK DLGWKWIHEP KGYHANFCLG PCPYIWSLDT QYSKVLALYN QHN PGASAA PCCVPQALEP LPIVYYVGRK PKVEQLSNMI VRSCKCS |
-Macromolecule #6: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 5 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 3 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #8: MAGNESIUM ION
Macromolecule | Name: MAGNESIUM ION / type: ligand / ID: 8 / Number of copies: 1 / Formula: MG |
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Molecular weight | Theoretical: 24.305 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Grid | Material: GRAPHENE OXIDE |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 70.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 43600 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |