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Yorodumi- EMDB-20794: Integrin alpha-v beta-8 in complex with latent TGF-beta (Primary ... -
+Open data
-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.) | ||||||||||||||||||||||||
Map data | Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation iv (Primary map: sharpened. Additional map: unsharpened.) | ||||||||||||||||||||||||
Sample |
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Keywords | glycoprotein / adhesion / signaling / SIGNALING PROTEIN | ||||||||||||||||||||||||
Function / homology | Function and homology information 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 / TGFBR3 regulates TGF-beta signaling / Downregulation of TGF-beta receptor signaling / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) ...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 / TGFBR3 regulates TGF-beta signaling / 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 / positive regulation of microglia differentiation / negative regulation of skeletal muscle tissue development / regulation of striated muscle tissue development / regulation of protein import into nucleus / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / Langerhans cell differentiation / extracellular matrix assembly / integrin alphav-beta8 complex / integrin alphav-beta6 complex / hard palate development / transforming growth factor beta production / odontoblast differentiation / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / opsonin binding / negative regulation of macrophage cytokine production / positive regulation of isotype switching to IgA isotypes / integrin alphav-beta1 complex / Cross-presentation of particulate exogenous antigens (phagosomes) / membrane protein intracellular domain proteolysis / extracellular matrix protein binding / hyaluronan catabolic process / receptor catabolic process / Laminin interactions / ATP biosynthetic process / placenta blood vessel development / negative regulation of lipoprotein metabolic process / integrin alphav-beta3 complex / negative regulation of low-density lipoprotein receptor activity / type II transforming growth factor beta receptor binding / alphav-beta3 integrin-PKCalpha complex / positive regulation of chemotaxis / alphav-beta3 integrin-HMGB1 complex / regulation of phagocytosis / type I transforming growth factor beta receptor binding / negative regulation of lipid transport / negative regulation of myoblast differentiation / cell-cell junction organization / Elastic fibre formation / alphav-beta3 integrin-IGF-1-IGF1R complex / response to cholesterol / transforming growth factor beta binding / entry into host cell by a symbiont-containing vacuole / positive regulation of small GTPase mediated signal transduction / filopodium membrane / extracellular matrix binding / phosphate-containing compound metabolic process / positive regulation of fibroblast migration / apolipoprotein A-I-mediated signaling pathway / apoptotic cell clearance / wound healing, spreading of epidermal cells / cartilage development / positive regulation of intracellular signal transduction / heterotypic cell-cell adhesion / integrin complex / Molecules associated with elastic fibres / microvillus membrane / cell adhesion mediated by integrin / positive regulation of epidermal growth factor receptor signaling pathway / negative chemotaxis / 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 cell division / positive regulation of SMAD protein signal transduction / lamellipodium membrane / negative regulation of blood vessel endothelial cell migration / fibronectin binding / negative regulation of macrophage derived foam cell differentiation / negative regulation of lipid storage / negative regulation of cell cycle / epithelial to mesenchymal transition / positive regulation of collagen biosynthetic process / ECM proteoglycans / positive regulation of blood vessel endothelial cell migration / voltage-gated calcium channel activity / Integrin cell surface interactions / hematopoietic progenitor cell differentiation / vasculogenesis / lymph node development / chondrocyte differentiation Similarity search - Function | ||||||||||||||||||||||||
Biological species | Homo sapiens (human) / Sus scrofa (pig) | ||||||||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.3 Å | ||||||||||||||||||||||||
Authors | Campbell MG / Cormier A | ||||||||||||||||||||||||
Funding support | United States, 7 items
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Citation | Journal: 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 |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | EM map: SurfViewMolmilJmol/JSmol |
Supplemental images |
-Downloads & links
-EMDB archive
Map data | emd_20794.map.gz | 1.6 MB | EMDB map data format | |
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Header (meta data) | emd-20794-v30.xml emd-20794.xml | 21.5 KB 21.5 KB | Display Display | EMDB header |
Images | emd_20794.png | 99.6 KB | ||
Filedesc metadata | emd-20794.cif.gz | 7.4 KB | ||
Others | emd_20794_additional.map.gz | 52.1 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-20794 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-20794 | HTTPS FTP |
-Validation report
Summary document | emd_20794_validation.pdf.gz | 319.7 KB | Display | EMDB validaton report |
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Full document | emd_20794_full_validation.pdf.gz | 319.3 KB | Display | |
Data in XML | emd_20794_validation.xml.gz | 6.5 KB | Display | |
Data in CIF | emd_20794_validation.cif.gz | 7.5 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-20794 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-20794 | HTTPS FTP |
-Related structure data
Related structure data | 6ujaMC 6ujbC 6ujcC C: citing same article (ref.) M: atomic model generated by this map |
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Similar structure data | |
EM raw data | EMPIAR-10343 (Title: CryoEM dataset containing multiple conformations of the asymmetric αVβ8 integrin bound to latent TGF-β on a holey carbon grid (strongly preferred orientations) 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]) EMPIAR-10344 (Title: CryoEM dataset containing multiple conformations of the asymmetric αVβ8 integrin bound to latent TGF-β on a graphene oxide grid (preferred orientations) 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]) |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_20794.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Annotation | Integrin alpha-v beta-8 in complex with latent TGF-beta, Conformation iv (Primary map: sharpened. Additional map: unsharpened.) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 |
-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: Homo sapiens (human) |
-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: Sus scrofa (pig) |
-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: Homo sapiens (human) |
Molecular weight | Theoretical: 112.813352 KDa |
Recombinant expression | Organism: Cricetulus griseus (Chinese hamster) |
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 UniProtKB: Integrin alpha-V |
-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: Homo sapiens (human) |
Molecular weight | Theoretical: 81.276664 KDa |
Recombinant expression | Organism: Cricetulus griseus (Chinese hamster) |
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 UniProtKB: Integrin beta-8 |
-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: Sus scrofa (pig) |
Molecular weight | Theoretical: 41.434449 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
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 UniProtKB: Transforming growth factor beta-1 proprotein |
-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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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.5 |
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Grid | Material: GRAPHENE OXIDE |
Vitrification | Cryogen name: ETHANE |
-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: FIELD EMISSION GUN |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
-Image processing
Startup model | Type of model: NONE |
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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 |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |