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- EMDB-33572: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2 -

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Basic information

Entry
Database: EMDB / ID: EMD-33572
TitleComplex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
Map data
Sample
  • Complex: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
    • Protein or peptide: Integrin alpha-V
    • Protein or peptide: Integrin beta-8
    • Protein or peptide: Transforming growth factor beta-1 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MANGANESE (II) ION
Function / homology
Function and homology information


ganglioside metabolic process / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / regulation of branching involved in mammary gland duct morphogenesis / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development / regulation of enamel mineralization ...ganglioside metabolic process / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / regulation of branching involved in mammary gland duct morphogenesis / positive regulation of microglia differentiation / Influenza Virus Induced Apoptosis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development / regulation of enamel mineralization / regulatory T cell differentiation / regulation of cartilage development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of blood vessel remodeling / tolerance induction to self antigen / 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 / embryonic liver development / columnar/cuboidal epithelial cell maturation / type III transforming growth factor beta receptor binding / positive regulation of odontogenesis / Langerhans cell differentiation / negative regulation of hyaluronan biosynthetic process / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / positive regulation of receptor signaling pathway via STAT / connective tissue replacement involved in inflammatory response wound healing / positive regulation of exit from mitosis / 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 / : / TGFBR2 Kinase Domain Mutants in Cancer / opsonin binding / positive regulation of smooth muscle cell differentiation / positive regulation of isotype switching to IgA isotypes / positive regulation of mesenchymal stem cell proliferation / integrin alphav-beta1 complex / mammary gland branching involved in thelarche / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / membrane protein intracellular domain proteolysis / heart valve morphogenesis / Cross-presentation of particulate exogenous antigens (phagosomes) / retina vasculature development in camera-type eye / extracellular matrix protein binding / response to laminar fluid shear stress / positive regulation of primary miRNA processing / positive regulation of vasculature development / bronchiole development / hyaluronan catabolic process / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / Laminin interactions / receptor catabolic process / positive regulation of branching involved in ureteric bud morphogenesis / positive regulation of extracellular matrix assembly / lens fiber cell differentiation / placenta blood vessel development / negative regulation of extracellular matrix disassembly / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / alphav-beta3 integrin-PKCalpha complex / entry into host cell by a symbiont-containing vacuole / response to salt / germ cell migration / negative regulation of biomineral tissue development / endoderm development / positive regulation of mononuclear cell migration / type I transforming growth factor beta receptor binding / alphav-beta3 integrin-HMGB1 complex / positive regulation of chemotaxis / phospholipid homeostasis / negative regulation of lipid transport / negative regulation of myoblast differentiation / positive regulation of endothelial cell apoptotic process / positive regulation of vascular permeability / negative regulation of low-density lipoprotein receptor activity / response to vitamin D / cell-cell junction organization / regulation of phagocytosis / Elastic fibre formation / positive regulation of regulatory T cell differentiation / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / response to cholesterol / digestive tract development / negative regulation of interleukin-17 production / surfactant homeostasis / deubiquitinase activator activity
Similarity search - Function
Transforming growth factor beta-1 proprotein / 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-1 proprotein / 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 Ig-like domain 2 / Integrin alpha chain / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / Integrins alpha chain signature. / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin alpha, N-terminal / Integrin domain superfamily / 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
Transforming growth factor beta-1 proprotein / Integrin alpha-V / Integrin beta-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsDuan Z / Zhang Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171201 China
CitationJournal: 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
DepositionJun 8, 2022-
Header (metadata) releaseAug 31, 2022-
Map releaseAug 31, 2022-
UpdateSep 7, 2022-
Current statusSep 7, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33572.png

Downloads & links

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Map

FileDownload / File: emd_33572.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.055 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.5264366 - 3.3923192
Average (Standard dev.)-0.0004552347 (±0.04740421)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 405.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33572_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33572_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2

EntireName: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
Components
  • Complex: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
    • Protein or peptide: Integrin alpha-V
    • Protein or peptide: Integrin beta-8
    • Protein or peptide: Transforming growth factor beta-1 proprotein
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2

SupramoleculeName: Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: Integrin alpha-V

MacromoleculeName: Integrin alpha-V / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.812711 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAFPPRRRLR LGPRGLPLLL SGLLLPLCRA FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKC DWSSTRRCQP IEFDATGNRD YAKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF L QDGTKTVE ...String:
MAFPPRRRLR LGPRGLPLLL SGLLLPLCRA FNLDVDSPAE YSGPEGSYFG FAVDFFVPSA SSRMFLLVGA PKANTTQPGI VEGGQVLKC DWSSTRRCQP IEFDATGNRD YAKDDPLEFK SHQWFGASVR SKQDKILACA PLYHWRTEMK QEREPVGTCF L QDGTKTVE YAPCRSQDID ADGQGFCQGG FSIDFTKADR VLLGGPGSFY WQGQLISDQV AEIVSKYDPN VYSIKYNNQL AT RTAQAIF DDSYLGYSVA VGDFNGDGID DFVSGVPRAA RTLGMVYIYD GKNMSSLYNF TGEQMAAYFG FSVAATDING DDY ADVFIG APLFMDRGSD GKLQEVGQVS VSLQRASGDF QTTKLNGFEV FARFGSAIAP LGDLDQDGFN DIAIAAPYGG EDKK GIVYI FNGRSTGLNA VPSQILEGQW AARSGCPPSF GYSMKGATDI DKNGYPDLIV GAFGVDRAIL YRARPVITVN AGLEV YPSI LNQDNKTCSL PGTALKVSCF NVRFCLKADG KGVLPRKLNF QVELLLDKLK QKGAIRRALF LYSRSPSHSK NMTISR GGL MQCEELIAYL RDESEFRDKL TPITIFMEYR LDYRTAADTT GLQPILNQFT PANISRQAHI LLDTGGLEVL FQ

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Macromolecule #2: Integrin beta-8

MacromoleculeName: Integrin beta-8 / type: protein_or_peptide / ID: 2
Details: The first 21 residues (MDMRVPAQLLGLLLLWFSGVL) are signal peptides.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.017355 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDMRVPAQLL GLLLLWFSGV LEDNRCASSN AASCARCLAL GPECGWCVQE DFISGGSRSE RCDIVSNLIS KGCSVDSIEY PSVHVIIPT ENEINTQVTP GEVSIQLRPG AEANFMLKVH PLKKYPVDLY YLVDVSASMH NNIEKLNSVG NDLSRKMAFF S RDFRLGFG ...String:
MDMRVPAQLL GLLLLWFSGV LEDNRCASSN AASCARCLAL GPECGWCVQE DFISGGSRSE RCDIVSNLIS KGCSVDSIEY PSVHVIIPT ENEINTQVTP GEVSIQLRPG AEANFMLKVH PLKKYPVDLY YLVDVSASMH NNIEKLNSVG NDLSRKMAFF S RDFRLGFG SYVDKTVSPY ISIHPERIHN QCSDYNLDCM PPHGYIHVLS LTENITEFEK AVHRQKISGN IDTPEGGFDA ML QAAVCES HIGWRKEAKR LLLVMTDQTS HLALDSKLAG IVCPNDGNCH LKNNVYVKST TMEHPSLGQL SEKLIDNNIN VIF AVQGKQ FHWYKDLLPL LPGTIAGEIE SKAANLNNLV VEAYQKLISE VKVQVENQVQ GIYFNITAIC PDGSRKPGME GCRN VTSND EVLFNVTVTM KKCDVTGGKN YAIIKPIGFN ETAKIHIHRN CSCQCEDNRG PKGKCVDETF LDSKCFQCDE NK

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Macromolecule #3: Transforming growth factor beta-1 proprotein

MacromoleculeName: Transforming growth factor beta-1 proprotein / type: protein_or_peptide / ID: 3
Details: The first 16 residues (MPLLLLLPLLWAGALA) are signal peptides.
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.010402 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPLLLLLPLL WAGALALSTC KTIDMELVKR KRIEAIRGQI LSKLRLASPP SQGEVPPGPL PEAVLALYNS TRDRVAGESA EPEPEPEAD YYAKEVTRVL MVETHNEIYD KFKQSTHSIY MFFNTSELRE AVPEPVLLSR AELRLLRLKL KVEQHVELYQ K YSNNSWRY ...String:
MPLLLLLPLL WAGALALSTC KTIDMELVKR KRIEAIRGQI LSKLRLASPP SQGEVPPGPL PEAVLALYNS TRDRVAGESA EPEPEPEAD YYAKEVTRVL MVETHNEIYD KFKQSTHSIY MFFNTSELRE AVPEPVLLSR AELRLLRLKL KVEQHVELYQ K YSNNSWRY LSNRLLAPSD SPEWLSFDVT GVVRQWLSRG GEIEGFRLSA HCSCDSRDNT LQVDINGFTT GRRGDLATIH GM NRPFLLL MATPLERAQH LQSSRHRRAL DTNYCFSSTE KNCCVRQLYI DFRKDLGWKW IHEPKGYHAN FCLGPCPYIW SLD TQYSKV LALYNQHNPG ASAAPCCVPQ ALEPLPIVYY VGRKPKVEQL SNMIVRSCKC S

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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: 5 / 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: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 9 / Number of copies: 1 / Formula: MN
Molecular weightTheoretical: 54.938 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

Concentration3 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 305011
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementProtocol: OTHER
Output model

PDB-7y1t:
Complex of integrin alphaV/beta8 and L-TGF-beta1 at a ratio of 1:2

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