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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
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


ganglioside metabolic process / cellular response to acetaldehyde / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / positive regulation of microglia differentiation / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / regulation of branching involved in mammary gland duct morphogenesis ...ganglioside metabolic process / cellular response to acetaldehyde / adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains / positive regulation of microglia differentiation / regulation of interleukin-23 production / branch elongation involved in mammary gland duct branching / positive regulation of primary miRNA processing / Influenza Virus Induced Apoptosis / negative regulation of skeletal muscle tissue development / regulation of branching involved in mammary gland duct morphogenesis / macrophage derived foam cell differentiation / frontal suture morphogenesis / regulation of enamel mineralization / regulation of cartilage development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of striated muscle tissue development / regulatory T cell differentiation / tolerance induction to self antigen / regulation of blood vessel remodeling / regulation of protein import into nucleus / embryonic liver development / extracellular matrix assembly / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / columnar/cuboidal epithelial cell maturation / negative regulation of hyaluronan biosynthetic process / type III transforming growth factor beta receptor binding / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / hard palate development / odontoblast differentiation / positive regulation of odontogenesis / connective tissue replacement involved in inflammatory response wound healing / Langerhans cell differentiation / negative regulation of macrophage cytokine production / positive regulation of smooth muscle cell differentiation / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of exit from mitosis / 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 / extracellular matrix protein binding / opsonin binding / positive regulation of isotype switching to IgA isotypes / positive regulation of mesenchymal stem cell proliferation / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / membrane protein intracellular domain proteolysis / positive regulation of receptor signaling pathway via STAT / heart valve morphogenesis / retina vasculature development in camera-type eye / integrin alphav-beta1 complex / TGFBR3 regulates TGF-beta signaling / mammary gland branching involved in thelarche / bronchiole development / Cross-presentation of particulate exogenous antigens (phagosomes) / hyaluronan catabolic process / positive regulation of vasculature development / response to laminar fluid shear stress / lens fiber cell differentiation / positive regulation of extracellular matrix assembly / negative regulation of extracellular matrix disassembly / ATP biosynthetic process / placenta blood vessel development / Laminin interactions / positive regulation of branching involved in ureteric bud morphogenesis / receptor catabolic process / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / negative regulation of lipoprotein metabolic process / integrin alphav-beta3 complex / type I transforming growth factor beta receptor binding / response to salt / entry into host cell by a symbiont-containing vacuole / germ cell migration / negative regulation of biomineral tissue development / alphav-beta3 integrin-PKCalpha complex / positive regulation of mononuclear cell migration / endoderm development / phospholipid homeostasis / alphav-beta3 integrin-HMGB1 complex / negative regulation of myoblast differentiation / positive regulation of chemotaxis / negative regulation of cell-cell adhesion mediated by cadherin / negative regulation of lipid transport / cell-cell junction organization / response to vitamin D / regulation of phagocytosis / : / response to cholesterol / positive regulation of vascular permeability / Elastic fibre formation / negative regulation of interleukin-17 production / alphav-beta3 integrin-IGF-1-IGF1R complex / surfactant homeostasis / deubiquitinase activator activity / transforming growth factor beta binding / phosphate-containing compound metabolic process
Similarity search - Function
Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / Teneurin-like EGF domain / 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-1 proprotein / Transforming growth factor-beta / Teneurin-like EGF domain / 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 EGF domain / Integrins beta chain EGF (I-EGF) domain profile. / Integrin alpha cytoplasmic region / 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 / Integrin alpha beta-propellor / Integrin alpha chain, C-terminal cytoplasmic region, conserved site / : / Integrin alpha Ig-like domain 2 / Integrins alpha chain signature. / FG-GAP repeat profile. / Integrin alpha (beta-propellor repeats). / FG-GAP repeat / FG-GAP repeat / Integrin domain superfamily / Integrin alpha, N-terminal / Cystine-knot cytokine / PSI domain / domain found in Plexins, Semaphorins and Integrins / von Willebrand factor A-like domain superfamily / EGF-like domain signature 1. / EGF-like domain signature 2. / 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-
UpdateNov 13, 2024-
Current statusNov 13, 2024Processing 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)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 384 pix.
= 405.12 Å		1.06 Å/pix.
x 384 pix.
= 405.12 Å		1.06 Å/pix.
x 384 pix.
= 405.12 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.055 Å
Density

Histogram

Histogram (log scale)
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

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Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33572_half_map_2.map
Projections & Slices
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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 / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)
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

UniProtKB: Integrin alpha-V

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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

UniProtKB: Integrin beta-8

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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

UniProtKB: Transforming growth factor beta-1 proprotein

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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

Startup modelType of model: NONE
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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