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- EMDB-33571: Human L-TGF-beta1 in complex with the anchor protein LRRC33 -

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Basic information

Entry
Database: EMDB / ID: EMD-33571
TitleHuman L-TGF-beta1 in complex with the anchor protein LRRC33
Map data
Sample
  • Complex: L-TGF-beta1 in complex with its anchor protein LRRC33
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Transforming growth factor beta activator LRRC33
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


: / sequestering of TGFbeta in extracellular matrix / 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 / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development ...: / sequestering of TGFbeta in extracellular matrix / 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 / Influenza Virus Induced Apoptosis / regulation of branching involved in mammary gland duct morphogenesis / frontal suture morphogenesis / negative regulation of skeletal muscle tissue development / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of enamel mineralization / regulatory T cell differentiation / regulation of cartilage development / regulation of blood vessel remodeling / regulation of striated muscle tissue development / tolerance induction to self antigen / 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 / negative regulation of hyaluronan biosynthetic process / Langerhans cell differentiation / positive regulation of odontogenesis / positive regulation of cardiac muscle cell differentiation / myofibroblast differentiation / connective tissue replacement involved in inflammatory response wound healing / extracellular matrix assembly / positive regulation of exit from mitosis / negative regulation of macrophage cytokine production / positive regulation of receptor signaling pathway via STAT / odontoblast differentiation / TGFBR2 Kinase Domain Mutants in Cancer / positive regulation of smooth muscle cell differentiation / positive regulation of mesenchymal stem cell proliferation / positive regulation of isotype switching to IgA isotypes / positive regulation of primary miRNA processing / mammary gland branching involved in thelarche / membrane protein intracellular domain proteolysis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / heart valve morphogenesis / response to laminar fluid shear stress / retina vasculature development in camera-type eye / positive regulation of vasculature development / hyaluronan catabolic process / bronchiole development / regulation of transforming growth factor beta receptor signaling pathway / ATP biosynthetic process / receptor catabolic process / positive regulation of branching involved in ureteric bud morphogenesis / negative regulation of extracellular matrix disassembly / positive regulation of extracellular matrix assembly / lens fiber cell differentiation / response to salt / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / oligodendrocyte development / germ cell migration / negative regulation of biomineral tissue development / type I transforming growth factor beta receptor binding / positive regulation of chemotaxis / phospholipid homeostasis / endoderm development / negative regulation of myoblast differentiation / positive regulation of mononuclear cell migration / cell-cell junction organization / response to vitamin D / positive regulation of vascular permeability / positive regulation of regulatory T cell differentiation / transforming growth factor beta binding / response to cholesterol / deubiquitinase activator activity / digestive tract development / positive regulation of endothelial cell apoptotic process / negative regulation of interleukin-17 production / microglia development / surfactant homeostasis / negative regulation of release of sequestered calcium ion into cytosol / positive regulation of fibroblast migration / negative regulation of ossification / positive regulation of chemokine (C-X-C motif) ligand 2 production / aortic valve morphogenesis / phosphate-containing compound metabolic process / negative regulation of phagocytosis / negative regulation of protein localization to plasma membrane / sprouting angiogenesis / neural tube development / face morphogenesis / Molecules associated with elastic fibres / RUNX3 regulates CDKN1A transcription / ureteric bud development / ventricular cardiac muscle tissue morphogenesis / cellular response to insulin-like growth factor stimulus / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of neuroblast proliferation / macrophage derived foam cell differentiation / Syndecan interactions / muscle cell cellular homeostasis
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. / Leucine Rich repeat / Cystine-knot cytokine / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Transforming growth factor beta-1 proprotein / Transforming growth factor beta activator LRRC33
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.01 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_33571.png

Downloads & links

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Map

FileDownload / File: emd_33571.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.055 Å
Density
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.0017771141 - 1.8793257
Average (Standard dev.)0.0013395529 (±0.02495337)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 270.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33571_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33571_half_map_2.map
Projections & Slices
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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 : L-TGF-beta1 in complex with its anchor protein LRRC33

EntireName: L-TGF-beta1 in complex with its anchor protein LRRC33
Components
  • Complex: L-TGF-beta1 in complex with its anchor protein LRRC33
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Transforming growth factor beta activator LRRC33
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: L-TGF-beta1 in complex with its anchor protein LRRC33

SupramoleculeName: L-TGF-beta1 in complex with its anchor protein LRRC33 / type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
Molecular weightTheoretical: 150 KDa

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Macromolecule #1: Transforming growth factor beta-1 proprotein

MacromoleculeName: Transforming growth factor beta-1 proprotein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / 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 #2: Transforming growth factor beta activator LRRC33

MacromoleculeName: Transforming growth factor beta activator LRRC33 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 72.191219 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MPLLLLLPLL WAGALAWRNR SGTATAASQG VCKLVGGAAD CRGQSLASVP SSLPPHARML TLDANPLKTL WNHSLQPYPL LESLSLHSC HLERISRGAF QEQGHLRSLV LGDNCLSENY EETAAALHAL PGLRRLDLSG NALTEDMAAL MLQNLSSLRS V SLAGNTIM ...String:
MPLLLLLPLL WAGALAWRNR SGTATAASQG VCKLVGGAAD CRGQSLASVP SSLPPHARML TLDANPLKTL WNHSLQPYPL LESLSLHSC HLERISRGAF QEQGHLRSLV LGDNCLSENY EETAAALHAL PGLRRLDLSG NALTEDMAAL MLQNLSSLRS V SLAGNTIM RLDDSVFEGL ERLRELDLQR NYIFEIEGGA FDGLAELRHL NLAFNNLPCI VDFGLTRLRV LNVSYNVLEW FL ATGGEAA FELETLDLSH NQLLFFPLLP QYSKLRTLLL RDNNMGFYRD LYNTSSPREM VAQFLLVDGN VTNITTVSLW EEF SSSDLA DLRFLDMSQN QFQYLPDGFL RKMPSLSHLN LHQNCLMTLH IREHEPPGAL TELDLSHNQL SELHLAPGLA SCLG SLRLF NLSSNQLLGV PPGLFANARN ITTLDMSHNQ ISLCPLPAAS DRVGPPSCVD FRNMASLRSL SLEGCGLGAL PDCPF QGTS LTYLDLSSNW GVLNGSLAPL QDVAPMLQVL SLRNMGLHSS FMALDFSGFG NLRDLDLSGN CLTTFPRFGG SLALET LDL RRNSLTALPQ KAVSEQLSRG LRTIYLSQNP YDCCGVDGWG ALQHGQTVAD WAMVTCNLSS KIIRVTELPG GVPRDCK WE RLDLGSNSLE VLFQ

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

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

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Image processing

Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.01 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 254673

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Atomic model buiding 1

RefinementProtocol: OTHER
Output model

PDB-7y1r:
Human L-TGF-beta1 in complex with the anchor protein LRRC33

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