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- PDB-6uja: Integrin alpha-v beta-8 in complex with pro-TGF-beta1 -

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Basic information

Entry
Database: PDB / ID: 6uja
TitleIntegrin alpha-v beta-8 in complex with pro-TGF-beta1
Components
  • Integrin alpha-VIntegrin alpha V
  • Integrin beta-8
  • Transforming growth factor beta-1 proprotein
KeywordsSIGNALING PROTEIN / glycoprotein / adhesion / signaling
Function / homology
Function and homology information


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 / 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 ...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 / 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 / regulation of branching involved in mammary gland duct morphogenesis / 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 enamel mineralization / positive regulation of microglia differentiation / regulation of DNA binding / regulation of cartilage development / tolerance induction to self antigen / negative regulation of skeletal muscle tissue development / columnar/cuboidal epithelial cell maturation / regulatory T cell differentiation / regulation of striated muscle tissue development / extracellular matrix assembly / positive regulation of odontogenesis / regulation of protein import into nucleus / Langerhans cell differentiation / embryonic liver development / type III transforming growth factor beta receptor binding / negative regulation of hyaluronan biosynthetic process / odontoblast differentiation / negative regulation of macrophage cytokine production / integrin alphav-beta6 complex / integrin alphav-beta8 complex / hard palate development / transforming growth factor beta production / negative regulation of entry of bacterium into host cell / integrin alphav-beta5 complex / mammary gland branching involved in thelarche / : / opsonin binding / positive regulation of isotype switching to IgA isotypes / integrin alphav-beta1 complex / membrane protein intracellular domain proteolysis / retina vasculature development in camera-type eye / Cross-presentation of particulate exogenous antigens (phagosomes) / bronchiole development / : / extracellular matrix protein binding / hyaluronan catabolic process / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / lens fiber cell differentiation / Laminin interactions / receptor catabolic process / positive regulation of extracellular matrix assembly / oligodendrocyte development / placenta blood vessel development / germ cell migration / integrin alphav-beta3 complex / negative regulation of lipoprotein metabolic process / type II transforming growth factor beta receptor binding / phospholipid homeostasis / endoderm development / positive regulation of chemotaxis / entry into host cell by a symbiont-containing vacuole / alphav-beta3 integrin-PKCalpha complex / type I transforming growth factor beta receptor binding / negative regulation of biomineral tissue development / alphav-beta3 integrin-HMGB1 complex / cell-cell junction organization / negative regulation of lipid transport / negative regulation of myoblast differentiation / negative regulation of low-density lipoprotein receptor activity / positive regulation of regulatory T cell differentiation / Elastic fibre formation / regulation of phagocytosis / : / negative regulation of interleukin-17 production / alphav-beta3 integrin-IGF-1-IGF1R complex / transforming growth factor beta binding / surfactant homeostasis / response to cholesterol / filopodium membrane / negative regulation of ossification / positive regulation of small GTPase mediated signal transduction / extracellular matrix binding / aortic valve morphogenesis / positive regulation of fibroblast migration / phosphate-containing compound metabolic process / apolipoprotein A-I-mediated signaling pathway / wound healing, spreading of epidermal cells / apoptotic cell clearance / cartilage development / face morphogenesis / heterotypic cell-cell adhesion / integrin complex / Molecules associated with elastic fibres
Similarity search - Function
Transforming growth factor beta-1 proprotein / Integrin domains. Chain A, domain 2 / Transforming growth factor-beta / Integrin alpha, N-terminal / 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-1 proprotein / Integrin domains. Chain A, domain 2 / Transforming growth factor-beta / Integrin alpha, N-terminal / 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 / von Willebrand factor, type A domain / : / 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 domain superfamily / Integrin alpha, N-terminal / Cystine-knot cytokine / PSI domain / domain found in Plexins, Semaphorins and Integrins / 7 Propeller / Methylamine Dehydrogenase; Chain H / von Willebrand factor A-like domain superfamily / EGF-like domain signature 2. / EGF-like domain signature 1. / EGF-like domain / Immunoglobulin-like / Sandwich / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Integrin alpha-V / Transforming growth factor beta-1 proprotein / Integrin beta-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Sus scrofa (pig)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCampbell, M.G. / Cormier, A. / Cheng, Y. / Nishimura, S.L.
Funding support United States, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)U54HL119893 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL113032 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL134183 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01GM098672 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)S10OD020054 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)S10OD021741 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P41CA196276 United States
CitationJournal: 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
DepositionOct 2, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / em_entity_assembly / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _em_entity_assembly.entity_id_list / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.src_method / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Assembly

Deposited unit
A: Integrin alpha-V
B: Integrin beta-8
D: Transforming growth factor beta-1 proprotein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)239,18317
Polymers235,5243
Non-polymers3,65914
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10000 Å2
ΔGint16 kcal/mol
Surface area50200 Å2

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Components

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Protein , 3 types, 3 molecules ABD

#1: Protein Integrin alpha-V / Integrin alpha V / Vitronectin receptor / Vitronectin receptor subunit alpha


Mass: 112813.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGAV, MSK8, VNRA, VTNR / Cell line (production host): CHO lec 3.2.8.1 / Production host: Cricetulus griseus (Chinese hamster) / Tissue (production host): ovary / References: UniProt: P06756
#2: Protein Integrin beta-8


Mass: 81276.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ITGB8 / Cell line (production host): CHO lec 3.2.8.1 / Production host: Cricetulus griseus (Chinese hamster) / Tissue (production host): ovary / References: UniProt: P26012
#3: Protein Transforming growth factor beta-1 proprotein


Mass: 41434.449 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Sus scrofa (pig) / Gene: TGFB1 / Cell line (production host): HEK293A / Organ (production host): kidney / Production host: Homo sapiens (human) / References: UniProt: P07200

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Sugars , 3 types, 8 molecules

#4: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-2DManpa1-3[DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-f1_d2-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}[(6+1)][a-D-Manp]{}}}}}LINUCSPDB-CARE
#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 6 molecules

#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Compound detailsLTGFb is a homodimer in the sample, but only a single chain (chain D) is modeled.
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSourceDetails
1Binary complex of Integrin alpha-v beta-8 with Latent TGF-beta-1 (L-TGF-b1)COMPLEX#1-#30MULTIPLE SOURCES
2alpha-v beta-8 integrinCOMPLEX#1-#21RECOMBINANT
3Transforming Growth Factor Beta-1 proproteinCOMPLEX#31RECOMBINANTLTGFb is a homodimer in the sample, but only a single chain is modeled.
Molecular weightValue: 0.26 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Sus scrofa (pig)9823
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Cricetulus griseus (Chinese hamster)10029
23Homo sapiens (human)9606HEK293A
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GRAPHENE OXIDE
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 70 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 43600 / Symmetry type: POINT

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