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- PDB-8tzo: Structure of human Wnt7a bound to WLS and CALR -

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Basic information

Entry
Database: PDB / ID: 8tzo
TitleStructure of human Wnt7a bound to WLS and CALR
Components
  • Calreticulin
  • Protein Wnt-7a
  • Protein wntless homolog
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


postsynapse assembly / positive regulation of excitatory synapse assembly / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / regulation of axon diameter / Wnt protein secretion / asymmetric protein localization involved in cell fate determination / response to biphenyl / Calnexin/calreticulin cycle / cytolytic granule ...postsynapse assembly / positive regulation of excitatory synapse assembly / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / regulation of axon diameter / Wnt protein secretion / asymmetric protein localization involved in cell fate determination / response to biphenyl / Calnexin/calreticulin cycle / cytolytic granule / positive regulation of Wnt protein secretion / lens fiber cell development / cerebellar granule cell differentiation / positive regulation of dendritic cell chemotaxis / WNT ligand biogenesis and trafficking / nuclear receptor-mediated glucocorticoid signaling pathway / oviduct development / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / synaptic vesicle recycling / central nervous system vasculogenesis / negative regulation of trophoblast cell migration / cell proliferation in forebrain / cortical granule / excitatory synapse assembly / uterus morphogenesis / complement component C1q complex binding / cellular response to electrical stimulus / response to peptide / embryonic axis specification / regulation of meiotic nuclear division / sequestering of calcium ion / cementum mineralization / negative regulation of retinoic acid receptor signaling pathway / secondary palate development / endoplasmic reticulum quality control compartment / presynapse assembly / somatic stem cell division / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / protein folding in endoplasmic reticulum / sarcoplasmic reticulum lumen / stem cell development / sex differentiation / hindbrain development / positive regulation of epithelial cell proliferation involved in wound healing / Wnt-protein binding / negative regulation of intracellular steroid hormone receptor signaling pathway / nuclear export signal receptor activity / cardiac muscle cell differentiation / establishment of blood-brain barrier / dendritic spine morphogenesis / frizzled binding / exocrine pancreas development / dorsal/ventral pattern formation / neurotransmitter secretion / embryonic forelimb morphogenesis / Class B/2 (Secretin family receptors) / regulation of postsynapse organization / embryonic hindlimb morphogenesis / positive regulation of synapse assembly / anterior/posterior axis specification / cortical actin cytoskeleton organization / response to glycoside / wound healing, spreading of epidermal cells / Wnt signaling pathway, planar cell polarity pathway / Scavenging by Class A Receptors / embryonic digit morphogenesis / nuclear androgen receptor binding / cartilage condensation / Scavenging by Class F Receptors / cellular response to lithium ion / negative regulation of neuron differentiation / establishment of cell polarity / response to testosterone / organelle membrane / midbrain development / regulation of synaptic vesicle exocytosis / positive regulation of protein metabolic process / smooth endoplasmic reticulum / hormone binding / mesoderm formation / molecular sequestering activity / somatic stem cell population maintenance / protein localization to nucleus / cell fate commitment / positive regulation of Wnt signaling pathway / positive regulation of excitatory postsynaptic potential / regulation of presynapse assembly / chondrocyte differentiation / canonical Wnt signaling pathway / cellular response to transforming growth factor beta stimulus / positive regulation of cell cycle / ERAD pathway / endocytic vesicle lumen / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of substrate adhesion-dependent cell spreading / protein folding chaperone / extracellular matrix / positive regulation of endothelial cell migration / peptide binding
Similarity search - Function
Wnt-7 protein / Protein wntless / : / : / Wntless-like, transmembrane domain / Wntless, GOLD domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain ...Wnt-7 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 / Protein Wnt-7a / Calreticulin / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 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 1.1May 8, 2024Group: Database references / Category: citation / citation_author
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Revision 1.2Oct 16, 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-7a
B: Protein wntless homolog
C: Calreticulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)151,8697
Polymers149,5793
Non-polymers2,2904
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-7a


Mass: 39062.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WNT7A / Production host: Homo sapiens (human) / References: UniProt: O00755
#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 , 3 types, 3 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
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca

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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: Wnt7a-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: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 276377 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038959
ELECTRON MICROSCOPYf_angle_d0.52712095
ELECTRON MICROSCOPYf_dihedral_angle_d8.7361245
ELECTRON MICROSCOPYf_chiral_restr0.0411300
ELECTRON MICROSCOPYf_plane_restr0.0051525

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