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- PDB-21kt: Wnt3a signalosome extracellular complex -

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Basic information

Entry
Database: PDB / ID: 21kt
TitleWnt3a signalosome extracellular complex
Components
  • Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR
  • Protein Wnt-3a
KeywordsSIGNALING PROTEIN / Wnt3a-Fzd8-LRP6 extracellular complex / cryo-EM structure / FKBP-independent Wnt3a homodimer
Function / homology
Function and homology information


positive regulation of dermatome development / calcium ion transmembrane transport via low voltage-gated calcium channel / positive regulation of collateral sprouting in absence of injury / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / axis elongation involved in somitogenesis / cell proliferation in midbrain / WNT ligand biogenesis and trafficking / positive regulation of biosynthetic process / spinal cord association neuron differentiation ...positive regulation of dermatome development / calcium ion transmembrane transport via low voltage-gated calcium channel / positive regulation of collateral sprouting in absence of injury / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / axis elongation involved in somitogenesis / cell proliferation in midbrain / WNT ligand biogenesis and trafficking / positive regulation of biosynthetic process / spinal cord association neuron differentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / positive regulation of multicellular organismal process / Wnt-Frizzled-LRP5/6 complex / negative regulation of axon extension involved in axon guidance / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / positive regulation of cell-cell adhesion mediated by cadherin / Signaling by RNF43 mutants / COP9 signalosome assembly / TCF dependent signaling in response to WNT / Transcriptional and post-translational regulation of MITF-M expression and activity / Regulation of FZD by ubiquitination / neural crest formation / kinase inhibitor activity / cell proliferation in forebrain / secondary palate development / regulation of RNA biosynthetic process / somatic stem cell division / cardiac muscle cell fate commitment / Wnt receptor activity / co-receptor binding / regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / macrolide binding / positive regulation of skeletal muscle tissue development / non-canonical Wnt signaling pathway / low-density lipoprotein particle receptor activity / activin receptor binding / TORC1 complex / Wnt-protein binding / toxin transmembrane transporter activity / negative regulation of dopaminergic neuron differentiation / regulation of postsynapse to nucleus signaling pathway / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / regulation of cellular response to stress / cytoplasmic side of membrane / cellular response to cholesterol / transforming growth factor beta receptor binding / positive regulation of cardiac muscle cell differentiation / TGFBR1 LBD Mutants in Cancer / post-anal tail morphogenesis / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / dopaminergic neuron differentiation / positive regulation of hepatocyte proliferation / midbrain dopaminergic neuron differentiation / signaling receptor inhibitor activity / mammary gland development / heart trabecula formation / frizzled binding / I-SMAD binding / Class B/2 (Secretin family receptors) / positive regulation of neural precursor cell proliferation / Wnt signalosome / determination of left/right symmetry / regulation of amyloid precursor protein catabolic process / terminal cisterna / ryanodine receptor complex / anterior/posterior pattern specification / Disassembly of the destruction complex and recruitment of AXIN to the membrane / inner ear morphogenesis / 'de novo' protein folding / neural crest cell differentiation / dorsal/ventral neural tube patterning / regulation of cell size / ventricular cardiac muscle tissue morphogenesis / FK506 binding / regulation of axonogenesis / negative regulation of fat cell differentiation / heart looping / midbrain development / regulation of synapse organization / mesoderm development / TGF-beta receptor signaling activates SMADs / negative regulation of smooth muscle cell apoptotic process / hemopoiesis / regulation of cell differentiation / regulation of lipid metabolic process / positive regulation of receptor internalization / mTORC1-mediated signalling / Calcineurin activates NFAT / skeletal muscle cell differentiation / cell fate commitment / regulation of immune response / protein serine/threonine kinase inhibitor activity / canonical Wnt signaling pathway / BMP signaling pathway / somitogenesis / regulation of presynapse assembly / neuronal dense core vesicle / heart morphogenesis / coreceptor activity
Similarity search - Function
Wnt-3 protein / Frizzled 8, cysteine-rich domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1 / Low density lipoprotein receptor-related protein 5/6 / : ...Wnt-3 protein / Frizzled 8, cysteine-rich domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1 / Low density lipoprotein receptor-related protein 5/6 / : / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / Rapamycin binding domain / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / Low-density lipoprotein receptor repeat class B / LDL-receptor class B (LDLRB) repeat profile. / LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Low-density lipoprotein receptor domain class A / : / FATC domain / PIK-related kinase, FAT / FAT domain / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / FATC / LDL-receptor class A (LDLRA) domain profile. / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / : / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Six-bladed beta-propeller, TolB-like / Coagulation Factor Xa inhibitory site / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Phosphatidylinositol 3- and 4-kinases signature 1. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Epidermal growth factor-like domain. / EGF-like domain signature 2. / EGF-like domain / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Serine/threonine-protein kinase mTOR / Low-density lipoprotein receptor-related protein 6 / Protein Wnt-3a / Peptidyl-prolyl cis-trans isomerase FKBP1A / Frizzled-8
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.33 Å
AuthorsYue, D. / Sun, G. / Zhang, L. / Wang, Z. / Xu, W.
Funding support China, 3items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
National Natural Science Foundation of China (NSFC) China
Ministry of Science and Technology (MoST, China) China
CitationJournal: Cell / Year: 2026
Title: Structural basis of Wnt signalosome extracellular complex assembly.
Authors: Dan Yue / Gangyu Sun / Yunlong Cao / Hongyue Li / Yufeng Yang / Zirun Pan / Lulu Xue / Lu Zhang / Zhizhi Wang / Wenqing Xu /
Abstract: Recognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains ...Recognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains enigmatic how Wnt simultaneously interacts with Fzd and LRP5/6 and activates intracellular Wnt/β-catenin signaling. Here, we report cryo-electron microscopy (cryo-EM) structures of Wnt3a/Fzd8/LRP6 extracellular complexes captured in a 2:4:2 stoichiometry, consisting of a Wnt3a-Wnt3a homodimer, whereby each Wnt3a monomer binds to two Fzd8 receptors and one LRP6 co-receptor. This implies that Wnt3a induces Fzd cystine-rich domain (Fzd-CRD) tetramerization, which in turn could promote recruitment of oligomeric Disheveled (Dvl) to Fzd on the cytoplasmic side. Indeed, mutations of key Wnt3a-Wnt3a interface residues abolish Fzd-LRP clustering and downstream signaling, supporting a critical role of Wnt3a-Wnt3a dimerization in Wnt signalosome assembly and signaling. Our structures also show how the Wnt3a N-helical domain recognizes the LRP6 extracellular domain (LRP6-ECD) E3 β-propeller, while the Wnt3a N-C hairpin interacts with the valley between LRP6-E3 and -E4 propellers, underpinning the development of targeted Wnt therapeutics.
History
DepositionDec 17, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 3, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 3, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein Wnt-3a
C: Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A
D: Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A
E: Protein Wnt-3a
F: Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR
H: Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A
G: Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A
B: Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)366,54015
Polymers364,3828
Non-polymers2,1587
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein Wnt-3a


Mass: 37438.258 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Wnt3a, Wnt-3a / Cell line (production host): L-Wnt3a cells / Production host: Mus musculus (house mouse) / References: UniProt: P27467
#2: Protein
Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A / Fz-8 / hFz8 / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / ...Fz-8 / hFz8 / PPIase FKBP1A / 12 kDa FK506-binding protein / 12 kDa FKBP / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 29762.502 Da / Num. of mol.: 4 / Mutation: Q159A,E161A,C178S,Q221A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FZD8, FKBP1A, FKBP1, FKBP12 / Production host: Homo sapiens (human)
References: UniProt: Q9H461, UniProt: P62942, peptidylprolyl isomerase
#3: Protein Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR / LRP-6


Mass: 85227.797 Da / Num. of mol.: 2 / Mutation: C715S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRP6, MTOR / Production host: Homo sapiens (human)
References: UniProt: O75581, UniProt: A0A8V8TRG9, non-specific serine/threonine protein kinase
#4: 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.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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
Has ligand of interestY
Has protein modificationY

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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-IDSource
1Ternary complex of Wnt3a with Fzd8-CRD and LRP6-E3E4COMPLEX#1-#30RECOMBINANT
2Wnt3aCOMPLEX#11RECOMBINANT
3Frizzled-8 and LRP6COMPLEX#2-#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Mus musculus (house mouse)10090
32Mus musculus (house mouse)10090
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Mus musculus (house mouse)10090
32Mus musculus (house mouse)10090
43Homo sapiens (human)9606
Buffer solutionpH: 7.5
SpecimenConc.: 1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Specimen holderCryogen: NITROGEN
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 3.33 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 230266 / Symmetry type: POINT
RefinementHighest resolution: 3.33 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00719464
ELECTRON MICROSCOPYf_angle_d0.726402
ELECTRON MICROSCOPYf_dihedral_angle_d6.5692686
ELECTRON MICROSCOPYf_chiral_restr0.0432836
ELECTRON MICROSCOPYf_plane_restr0.0043452

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