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- PDB-8tzr: Structure of human Wnt3a bound to WLS and CALR -

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Basic information

Entry
Database: PDB / ID: 8tzr
TitleStructure of human Wnt3a bound to WLS and CALR
Components
  • Calreticulin
  • Protein Wnt-3a
  • Protein wntless homolog
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


Wnt signaling pathway involved in forebrain neuroblast division / 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 / spinal cord association neuron differentiation / Wnt protein secretion ...Wnt signaling pathway involved in forebrain neuroblast division / 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 / spinal cord association neuron differentiation / Wnt protein secretion / positive regulation of type B pancreatic cell proliferation / Formation of the posterior neural plate / Calnexin/calreticulin cycle / response to biphenyl / COP9 signalosome assembly / cytolytic granule / Wnt-Frizzled-LRP5/6 complex / positive regulation of Wnt protein secretion / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / positive regulation of cell-cell adhesion mediated by cadherin / positive regulation of dendritic cell chemotaxis / WNT ligand biogenesis and trafficking / ATF6 (ATF6-alpha) activates chaperone genes / Signaling by RNF43 mutants / Assembly of Viral Components at the Budding Site / negative regulation of axon extension involved in axon guidance / synaptic vesicle recycling / cortical granule / negative regulation of trophoblast cell migration / cell proliferation in forebrain / positive regulation of cardiac muscle cell differentiation / nuclear receptor-mediated glucocorticoid signaling pathway / cellular response to electrical stimulus / complement component C1q complex binding / response to peptide / Specification of the neural plate border / regulation of meiotic nuclear division / negative regulation of retinoic acid receptor signaling pathway / cementum mineralization / sequestering of calcium ion / endoplasmic reticulum quality control compartment / secondary palate development / somatic stem cell division / protein folding in endoplasmic reticulum / cardiac muscle cell fate commitment / sarcoplasmic reticulum lumen / non-canonical Wnt signaling pathway / co-receptor binding / response to glycoside / presynapse assembly / hindbrain development / positive regulation of skeletal muscle tissue development / negative regulation of dopaminergic neuron differentiation / hormone binding / Wnt-protein binding / negative regulation of intracellular steroid hormone receptor signaling pathway / midbrain dopaminergic neuron differentiation / nuclear export signal receptor activity / dorsal/ventral neural tube patterning / regulation of postsynapse to nucleus signaling pathway / cardiac muscle cell differentiation / post-anal tail morphogenesis / mammary gland development / exocrine pancreas development / positive regulation of neural precursor cell proliferation / frizzled binding / myoblast differentiation / Class B/2 (Secretin family receptors) / positive regulation of hepatocyte proliferation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / anterior/posterior axis specification / cortical actin cytoskeleton organization / Scavenging by Class A Receptors / inner ear morphogenesis / nuclear androgen receptor binding / Scavenging by Class F Receptors / cellular response to lithium ion / negative regulation of fat cell differentiation / regulation of synapse organization / midbrain development / Formation of paraxial mesoderm / organelle membrane / fat cell differentiation / heart looping / response to testosterone / skeletal muscle cell differentiation / hemopoiesis / B cell proliferation / mesoderm formation / molecular sequestering activity / positive regulation of receptor internalization / regulation of presynapse assembly / positive regulation of Wnt signaling pathway / cell fate commitment / negative regulation of neuron differentiation / protein localization to nucleus / canonical Wnt signaling pathway / smooth endoplasmic reticulum / positive regulation of phagocytosis / cellular response to retinoic acid
Similarity search - Function
Wnt-3 protein / Protein wntless / : / : / Wntless-like, transmembrane domain / Wntless, GOLD domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain ...Wnt-3 protein / Protein wntless / : / : / Wntless-like, transmembrane domain / Wntless, GOLD domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1 / Calreticulin / Calreticulin family repeated motif signature. / Calreticulin/calnexin / Calreticulin/calnexin, P domain superfamily / Calreticulin/calnexin, conserved site / Calreticulin family / Calreticulin family signature 1. / Calreticulin family signature 2. / Endoplasmic reticulum targeting sequence. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
PALMITOLEIC ACID / Chem-POV / Calreticulin / Protein Wnt-3a / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsQi, X. / Hu, Q. / Li, X.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM135343 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)HL160487 United States
Welch FoundationI-1957 United States
CitationJournal: Cell / Year: 2023
Title: Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.
Authors: Xiaofeng Qi / Qinli Hu / Nadia Elghobashi-Meinhardt / Tao Long / Hongwen Chen / Xiaochun Li /
Abstract: Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility ...Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECK engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.
History
DepositionAug 27, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 18, 2023Provider: repository / Type: Initial release
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Revision 1.1Oct 23, 2024Group: Data collection / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein Wnt-3a
B: Protein wntless homolog
C: Calreticulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)152,1886
Polymers149,9383
Non-polymers2,2503
Water00
1


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

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein Protein Wnt-3a


Mass: 39421.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WNT3A / Production host: Homo sapiens (human) / References: UniProt: P56704
#2: Protein Protein wntless homolog


Mass: 62317.973 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WLS / Production host: Homo sapiens (human) / References: UniProt: Q5T9L3
#3: Protein Calreticulin


Mass: 48198.379 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P27797

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Sugars , 1 types, 1 molecules

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


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpa1-3DManpa1-2DManpa1-2DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/4,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5][a2122h-1a_1-5]/1-1-2-3-3-3-4/a4-b1_b4-c1_c3-d1_d2-e1_e2-f1_f3-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(3+1)][a-D-Glcp]{}}}}}}}LINUCSPDB-CARE

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-PAM / PALMITOLEIC ACID


Mass: 254.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H30O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C42H82NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM

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Details

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

ComponentName: Wnt3a-WLS-CALR Complex / Type: COMPLEX / Entity ID: #1-#3 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
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 FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113802 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059055
ELECTRON MICROSCOPYf_angle_d0.70812228
ELECTRON MICROSCOPYf_dihedral_angle_d9.4531261
ELECTRON MICROSCOPYf_chiral_restr0.0451302
ELECTRON MICROSCOPYf_plane_restr0.0051550

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