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- EMDB-53558: pro-TGF-beta1 in complex with the third TB Domain from Latent Tra... -

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Basic information

Entry
Database: EMDB / ID: EMD-53558
Titlepro-TGF-beta1 in complex with the third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1
Map data
Sample
  • Complex: Complex of pro-Transforming growth factor beta 1 and the third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Latent-transforming growth factor beta-binding protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water
KeywordsLatent transforming growth factor TGF-beta1 / LTBP1 / mechanobiology / extracellular matrix protein / disulphide / CYTOKINE / SIGNALING PROTEIN
Function / homology
Function and homology information


establishment of protein localization to extracellular region / protein localization to extracellular region / elastic fiber / frontal suture morphogenesis / Influenza Virus Induced Apoptosis / 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 / positive regulation of primary miRNA processing / morphogenesis of a branching structure ...establishment of protein localization to extracellular region / protein localization to extracellular region / elastic fiber / frontal suture morphogenesis / Influenza Virus Induced Apoptosis / 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 / positive regulation of primary miRNA processing / morphogenesis of a branching structure / negative regulation of skeletal muscle tissue development / embryonic liver development / negative regulation of MyD88-dependent toll-like receptor signaling pathway / regulation of striated muscle tissue development / response to laminar fluid shear stress / heart valve morphogenesis / macrophage derived foam cell differentiation / TGFBR2 MSI Frameshift Mutants in Cancer / regulation of protein import into nucleus / regulation of blood vessel remodeling / transforming growth factor beta complex / negative regulation of macrophage cytokine production / cellular response to acetaldehyde / connective tissue replacement involved in inflammatory response wound healing / negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target / negative regulation of hyaluronan biosynthetic process / extracellular matrix assembly / non-collagenous component of basement membrane / microfibril binding / type III transforming growth factor beta receptor binding / microfibril / myofibroblast differentiation / transforming growth factor beta receptor activity / TGFBR2 Kinase Domain Mutants in Cancer / odontoblast differentiation / positive regulation of exit from mitosis / salivary gland morphogenesis / positive regulation of isotype switching to IgA isotypes / negative regulation of neuroblast proliferation / transforming growth factor beta production / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / positive regulation of mesenchymal stem cell proliferation / positive regulation of receptor signaling pathway via STAT / membrane protein intracellular domain proteolysis / positive regulation of extracellular matrix assembly / negative regulation of myoblast differentiation / TGFBR3 regulates TGF-beta signaling / neural tube development / positive regulation of vasculature development / hyaluronan catabolic process / ATP biosynthetic process / cell-cell junction organization / type II transforming growth factor beta receptor binding / negative regulation of extracellular matrix disassembly / positive regulation of branching involved in ureteric bud morphogenesis / receptor catabolic process / response to salt / positive regulation of cardiac muscle cell differentiation / TGFBR1 LBD Mutants in Cancer / regulatory T cell differentiation / positive regulation of chemotaxis / negative regulation of cell-cell adhesion mediated by cadherin / type I transforming growth factor beta receptor binding / negative regulation of biomineral tissue development / ureteric bud development / positive regulation of vascular permeability / receptor ligand inhibitor activity / oligodendrocyte development / positive regulation of mononuclear cell migration / response to vitamin D / odontogenesis of dentin-containing tooth / negative regulation of interleukin-17 production / face morphogenesis / digestive tract development / response to cholesterol / sprouting angiogenesis / transforming growth factor beta binding / phosphate-containing compound metabolic process / chondrocyte differentiation / positive regulation of chemokine (C-X-C motif) ligand 2 production / lymph node development / positive regulation of fibroblast migration / aortic valve morphogenesis / RUNX3 regulates CDKN1A transcription / positive regulation of interleukin-17 production / positive regulation of regulatory T cell differentiation / negative regulation of fat cell differentiation / negative regulation of release of sequestered calcium ion into cytosol / Molecules associated with elastic fibres / cellular response to dexamethasone stimulus / neural tube closure / cellular response to insulin-like growth factor stimulus / Syndecan interactions / negative regulation of cell cycle / inner ear development / ventricular cardiac muscle tissue morphogenesis / negative regulation of phagocytosis / response to immobilization stress / positive regulation of epidermal growth factor receptor signaling pathway
Similarity search - Function
: / TB domain / TB domain / TGF-beta binding (TB) domain superfamily / TGF-beta binding (TB) domain profile. / Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / Complement Clr-like EGF domain / Complement Clr-like EGF-like / TGF-beta, propeptide ...: / TB domain / TB domain / TGF-beta binding (TB) domain superfamily / TGF-beta binding (TB) domain profile. / Transforming growth factor beta-1 proprotein / Transforming growth factor-beta / Complement Clr-like EGF domain / Complement Clr-like EGF-like / 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. / : / Calcium-binding EGF domain / Cystine-knot cytokine / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / EGF-like domain profile. / Growth factor receptor cysteine-rich 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 / Latent-transforming growth factor beta-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.06 Å
AuthorsBiggin G / Snee M / Godwin A / Roseman A / Baldock C
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Biotechnology and Biological Sciences Research Council (BBSRC) United Kingdom
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for the contribution of latent TGFβ binding protein to TGFβ latency and activation.
Authors: George R Biggin / Matthew Snee / Yu-Bai Xiao / Catherine Smedley / Alan R F Godwin / Rana Dajani / Holly L Birchenough / Thomas A Jowitt / Mark A Travis / Alan M Roseman / Anna Tarakanova / Clair Baldock /
Abstract: Transforming growth factor-β (TGFβ) is a potent cytokine that controls all aspects of cellular behavior. TGFβ is secreted in complex with its prodomain and latent TGFβ-binding protein-1 (LTBP1), ...Transforming growth factor-β (TGFβ) is a potent cytokine that controls all aspects of cellular behavior. TGFβ is secreted in complex with its prodomain and latent TGFβ-binding protein-1 (LTBP1), forming the large latent complex (LLC), which through interaction with the extracellular matrix enables integrin-mediated activation. Although TGFβ structures are known, the influence of LTBP1 on the structure and activity of TGFβ is unknown. Here, we report the LLC cryo-EM structure comprising the LTBP1 eight-cysteine domain covalently bound to TGFβ, revealing a hydrophobic interface between TGFβ and LTBP1. Structure-guided mutagenesis shows that the interface is important for complex formation and TGFβ activity. Our structure supports a contralateral domain swapped architecture in the LLC, and simulations show that this architecture requires increased force to overcome barriers for integrin-mediated activation, while the covalent attachment of TGFβ to LTBP1 redistributes force to reduce unfolding barriers. These insights will be important for therapeutic strategies targeting TGFβ.
History
DepositionMay 6, 2025-
Header (metadata) releaseJul 22, 2026-
Map releaseJul 22, 2026-
UpdateAug 19, 2026-
Current statusAug 19, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_53558.png

Downloads & links

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Map

FileDownload / File: emd_53558.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å		1.08 Å/pix.
x 256 pix.
= 276.48 Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0821
Minimum - Maximum-0.56432754 - 1.2312499
Average (Standard dev.)-0.00044123438 (±0.02005487)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_53558_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_53558_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of pro-Transforming growth factor beta 1 and the third TB...

EntireName: Complex of pro-Transforming growth factor beta 1 and the third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1
Components
  • Complex: Complex of pro-Transforming growth factor beta 1 and the third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1
    • Protein or peptide: Transforming growth factor beta-1 proprotein
    • Protein or peptide: Latent-transforming growth factor beta-binding protein 1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: water

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Supramolecule #1: Complex of pro-Transforming growth factor beta 1 and the third TB...

SupramoleculeName: Complex of pro-Transforming growth factor beta 1 and the third TB Domain from Latent Transforming Growth Factor-beta Binding Protein-1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: This structure represents the resolvable portion of a sample containing pro-TGF-beta 1 disulphide bonded to a region of LTBP1. A fragment of fibrillin-1 was in the sample but fibrillin-1 was not resolved.
Source (natural)Organism: Homo sapiens (human)

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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: 42.320191 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDKLS TCKTIDMELV KRKRIEAIRG QILSKLRLAS PPSQGEVPPG PLPEAVLALY NSTRDRVAGE SAEPEPEPEA DYYAKEVTR VLMVETHNEI YDKFKQSTHS IYMFFNTSEL REAVPEPVLL SRAELRLLRL KLKVEQHVEL YQKYSNNSWR Y LSNRLLAP ...String:
DYKDDDDKLS TCKTIDMELV KRKRIEAIRG QILSKLRLAS PPSQGEVPPG PLPEAVLALY NSTRDRVAGE SAEPEPEPEA DYYAKEVTR VLMVETHNEI YDKFKQSTHS IYMFFNTSEL REAVPEPVLL SRAELRLLRL KLKVEQHVEL YQKYSNNSWR Y LSNRLLAP SDSPEWLSFD VTGVVRQWLS RGGEIEGFRL SAHCSCDSRD NTLQVDINGF TTGRRGDLAT IHGMNRPFLL LM ATPLERA QHLQSSRHRR ALDTNYCFSS TEKNCCVRQL YIDFRKDLGW KWIHEPKGYH ANFCLGPCPY IWSLDTQYSK VLA LYNQHN PGASAAPCCV PQALEPLPIV YYVGRKPKVE QLSNMIVRSC KCS

UniProtKB: Transforming growth factor beta-1 proprotein

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Macromolecule #2: Latent-transforming growth factor beta-binding protein 1

MacromoleculeName: Latent-transforming growth factor beta-binding protein 1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 47.603562 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: APLALDVDVD QPKEEKKECY YNLNDASLCD NVLAPNVTKQ ECCCTSGVGW GDNCEIFPCP VLGTAEFTEM CPKGKGFVPA GESSSEAGG ENYKDADECL LFGQEICKNG FCLNTRPGYE CYCKQGTYYD PVKLQCFDMD ECQDPSSCID GQCVNTEGSY N CFCTHPMV ...String:
APLALDVDVD QPKEEKKECY YNLNDASLCD NVLAPNVTKQ ECCCTSGVGW GDNCEIFPCP VLGTAEFTEM CPKGKGFVPA GESSSEAGG ENYKDADECL LFGQEICKNG FCLNTRPGYE CYCKQGTYYD PVKLQCFDMD ECQDPSSCID GQCVNTEGSY N CFCTHPMV LDASEKRCIR PAESNEQIEE TDVYQDLCWE HLSDEYVCSR PLVGKQTTYT ECCCLYGEAW GMQCALCPLK DS DDYAQLC NIPVTGRRQP YGRDALVDFS EQYTPEADPY FIQDRFLNSF EELQAEECGI LNGCENGRCV RVQEGYTCDC FDG YHLDTA KMTCVDVNEC DELNNRMSLC KNAKCINTDG SYKCLCLPGY VPSDKPNYCT PLNTALNLEK DSDLTGGGGS GGGG SGGGG SAWSHPQFEK GGGSGGGSGG SAWSHPQFEK

UniProtKB: Latent-transforming growth factor beta-binding protein 1

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 1 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 41 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration1 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
20.0 mMHEPESHEPES
150.0 mMNaClsodium chloride

Details: 20mM HEPES, 150mM NaCl, pH 7.4
GridModel: Quantifoil R2/2 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK II / Details: Vitrification carried out in liquid ethane.
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 30000 / Average exposure time: 3.22 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.75 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 92789 / Details: Automated blob picker - cryoSPARC
CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 3.06 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 124397
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC / Details: ab initio
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final 3D classificationNumber classes: 50 / Avg.num./class: 1670 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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