+Open data
-Basic information
Entry | Database: PDB / ID: 7y1r | ||||||
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Title | Human L-TGF-beta1 in complex with the anchor protein LRRC33 | ||||||
Components | (Transforming growth factor ...) x 2 | ||||||
Keywords | SIGNALING PROTEIN / NRROS / anchor protein | ||||||
Function / homology | Function and homology information : / sequestering of TGFbeta in extracellular matrix / positive regulation of primary miRNA processing / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / TGFBR2 MSI Frameshift Mutants in Cancer / regulatory T cell differentiation / regulation of blood vessel remodeling / regulation of striated muscle tissue development ...: / sequestering of TGFbeta in extracellular matrix / positive regulation of primary miRNA processing / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / TGFBR2 MSI Frameshift Mutants in Cancer / regulatory T cell differentiation / regulation of blood vessel remodeling / regulation of striated muscle tissue development / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / regulation of protein import into nucleus / extracellular matrix assembly / embryonic liver development / type III transforming growth factor beta receptor binding / negative regulation of hyaluronan biosynthetic process / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / connective tissue replacement involved in inflammatory response wound healing / odontoblast differentiation / negative regulation of macrophage cytokine production / positive regulation of receptor signaling pathway via STAT / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of isotype switching to IgA isotypes / positive regulation of mesenchymal stem cell proliferation / membrane protein intracellular domain proteolysis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / heart valve morphogenesis / positive regulation of vasculature development / hyaluronan catabolic process / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / receptor catabolic process / negative regulation of extracellular matrix disassembly / positive regulation of extracellular matrix assembly / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / positive regulation of chemotaxis / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / cell-cell junction organization / negative regulation of myoblast differentiation / positive regulation of vascular permeability / deubiquitinase activator activity / transforming growth factor beta binding / response to cholesterol / positive regulation of endothelial cell apoptotic process / microglia development / positive regulation of chemokine (C-X-C motif) ligand 2 production / aortic valve morphogenesis / positive regulation of fibroblast migration / phosphate-containing compound metabolic process / negative regulation of protein localization to plasma membrane / sprouting angiogenesis / neural tube development / Molecules associated with elastic fibres / RUNX3 regulates CDKN1A transcription / positive regulation of epidermal growth factor receptor signaling pathway / ventricular cardiac muscle tissue morphogenesis / macrophage derived foam cell differentiation / negative regulation of fat cell differentiation / Syndecan interactions / superoxide metabolic process / negative regulation of cell-cell adhesion / positive regulation of interleukin-17 production / TGF-beta receptor signaling activates SMADs / negative regulation of cell differentiation / positive regulation of SMAD protein signal transduction / RUNX3 regulates p14-ARF / positive regulation of cell division / cellular response to low-density lipoprotein particle stimulus / negative regulation of blood vessel endothelial cell migration / negative regulation of cell cycle / ECM proteoglycans / positive regulation of vascular endothelial growth factor production / positive regulation of collagen biosynthetic process / epithelial to mesenchymal transition / positive regulation of epithelial to mesenchymal transition / positive regulation of blood vessel endothelial cell migration / vasculogenesis / lymph node development / chondrocyte differentiation / hematopoietic progenitor cell differentiation / salivary gland morphogenesis / extrinsic apoptotic signaling pathway / positive regulation of protein dephosphorylation / regulation of cell migration / cellular response to transforming growth factor beta stimulus / antigen binding / positive regulation of protein metabolic process / protein export from nucleus / Downregulation of TGF-beta receptor signaling / extracellular matrix / transforming growth factor beta receptor signaling pathway / positive regulation of superoxide anion generation / negative regulation of miRNA transcription / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / negative regulation of protein phosphorylation / platelet alpha granule lumen Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.01 Å | ||||||
Authors | Duan, Z. / Zhang, Z. | ||||||
Funding support | China, 1items
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Citation | Journal: Nat Commun / Year: 2022 Title: Specificity of TGF-β1 signal designated by LRRC33 and integrin αβ. Authors: Zelin Duan / Xuezhen Lin / Lixia Wang / Qiuxin Zhen / Yuefeng Jiang / Chuxin Chen / Jing Yang / Chia-Hsueh Lee / Yan Qin / Ying Li / Bo Zhao / Jianchuan Wang / Zhe Zhang / Abstract: Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ activates extracellular L-TGF-β1 to trigger ...Myeloid lineage cells present the latent form of transforming growth factor-β1 (L-TGF-β1) to the membrane using an anchor protein LRRC33. Integrin αβ activates extracellular L-TGF-β1 to trigger the downstream signaling functions. However, the mechanism designating the specificity of TGF-β1 presentation and activation remains incompletely understood. Here, we report cryo-EM structures of human L-TGF-β1/LRRC33 and integrin αβ/L-TGF-β1 complexes. Combined with biochemical and cell-based analyses, we demonstrate that LRRC33 only presents L-TGF-β1 but not the -β2 or -β3 isoforms due to difference of key residues on the growth factor domains. Moreover, we reveal a 2:2 binding mode of integrin αβ and L-TGF-β1, which shows higher avidity and more efficient L-TGF-β1 activation than previously reported 1:2 binding mode. We also uncover that the disulfide-linked loop of the integrin subunit β determines its exquisite affinity to L-TGF-β1. Together, our findings provide important insights into the specificity of TGF-β1 signaling achieved by LRRC33 and integrin αβ. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 7y1r.cif.gz | 199.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7y1r.ent.gz | 160 KB | Display | PDB format |
PDBx/mmJSON format | 7y1r.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/y1/7y1r ftp://data.pdbj.org/pub/pdb/validation_reports/y1/7y1r | HTTPS FTP |
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-Related structure data
Related structure data | 33571MC 7y1tC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Transforming growth factor ... , 2 types, 3 molecules ABE
#1: Protein | Mass: 43010.402 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: TGFB1 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01137 #2: Protein | | Mass: 72191.219 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: LRRC33 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q86YC3 |
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-Sugars , 4 types, 8 molecules
#3: Polysaccharide | beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #4: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #6: Sugar | ChemComp-NAG / | |
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-Details
Has ligand of interest | Y |
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Sequence details | The first 16 residues of chain A, B, and E (MPLLLLLPLL |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: L-TGF-beta1 in complex with its anchor protein LRRC33 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.15 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) / Cell: HEK293 |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Specimen support | Grid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3 |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1200 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
EM software | Name: SerialEM / Category: image acquisition |
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CTF correction | Type: NONE |
3D reconstruction | Resolution: 4.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 254673 / Symmetry type: POINT |
Atomic model building | Protocol: OTHER |