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- PDB-8tzp: Structure of human Wnt7a bound to WLS and RECK -

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Basic information

Entry
Database: PDB / ID: 8tzp
TitleStructure of human Wnt7a bound to WLS and RECK
Components
  • Protein Wnt-7a
  • Protein wntless homolog
  • Reversion-inducing cysteine-rich protein with Kazal motifs
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


regulation of establishment of blood-brain barrier / : / postsynapse assembly / negative regulation of metalloendopeptidase activity / positive regulation of excitatory synapse assembly / regulation of axon diameter / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / asymmetric protein localization involved in cell fate determination ...regulation of establishment of blood-brain barrier / : / postsynapse assembly / negative regulation of metalloendopeptidase activity / positive regulation of excitatory synapse assembly / regulation of axon diameter / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / asymmetric protein localization involved in cell fate determination / excitatory synapse assembly / cerebellar granule cell differentiation / blood vessel maturation / lens fiber cell development / positive regulation of Wnt protein secretion / synaptic vesicle recycling / WNT ligand biogenesis and trafficking / oviduct development / central nervous system vasculogenesis / cell proliferation in forebrain / uterus morphogenesis / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / secondary palate development / embryonic axis specification / Post-translational modification: synthesis of GPI-anchored proteins / cementum mineralization / metalloendopeptidase inhibitor activity / somatic stem cell division / presynapse assembly / sex differentiation / positive regulation of epithelial cell proliferation involved in wound healing / hindbrain development / stem cell development / Wnt-protein binding / establishment of blood-brain barrier / exocrine pancreas development / neurotransmitter secretion / dendritic spine morphogenesis / frizzled binding / dorsal/ventral pattern formation / embryonic forelimb morphogenesis / Wnt signalosome / Class B/2 (Secretin family receptors) / embryonic hindlimb morphogenesis / positive regulation of synapse assembly / wound healing, spreading of epidermal cells / sprouting angiogenesis / Wnt signaling pathway, planar cell polarity pathway / anterior/posterior axis specification / regulation of postsynapse organization / midbrain development / regulation of synaptic vesicle exocytosis / embryonic digit morphogenesis / cartilage condensation / endopeptidase inhibitor activity / establishment of cell polarity / somatic stem cell population maintenance / positive regulation of excitatory postsynaptic potential / regulation of presynapse assembly / mesoderm formation / positive regulation of Wnt signaling pathway / canonical Wnt signaling pathway / cell fate commitment / endomembrane system / regulation of angiogenesis / chondrocyte differentiation / side of membrane / cellular response to transforming growth factor beta stimulus / positive regulation of protein metabolic process / embryo implantation / positive regulation of endothelial cell migration / extracellular matrix organization / negative regulation of cell migration / axonogenesis / extracellular matrix / cytokine activity / positive regulation of JNK cascade / intracellular protein transport / Schaffer collateral - CA1 synapse / serine-type endopeptidase inhibitor activity / neuron differentiation / trans-Golgi network / Wnt signaling pathway / negative regulation of neurogenesis / Golgi lumen / response to estrogen / endocytic vesicle membrane / positive regulation of canonical Wnt signaling pathway / presynapse / response to estradiol / early endosome membrane / cytoplasmic vesicle / angiogenesis / positive regulation of canonical NF-kappaB signal transduction / early endosome / receptor ligand activity / endoplasmic reticulum lumen / Golgi membrane / signaling receptor binding / glutamatergic synapse
Similarity search - Function
Reversion-inducing cysteine-rich protein with Kazal motifs / Wnt-7 protein / Protein wntless / : / Wntless-like, transmembrane domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family ...Reversion-inducing cysteine-rich protein with Kazal motifs / Wnt-7 protein / Protein wntless / : / Wntless-like, transmembrane domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1 / Kazal-type serine protease inhibitor domain / Kazal serine protease inhibitors family signature. / Kazal type serine protease inhibitors / Kazal domain superfamily / Kazal domain / Kazal domain profile.
Similarity search - Domain/homology
PALMITOLEIC ACID / Chem-POV / Protein Wnt-7a / Reversion-inducing cysteine-rich protein with Kazal motifs / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 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
Revision 1.1May 8, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein Wnt-7a
B: Protein wntless homolog
C: Reversion-inducing cysteine-rich protein with Kazal motifs
hetero molecules


Theoretical massNumber of molelcules
Total (without water)208,9695
Polymers207,9543
Non-polymers1,0142
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#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 Reversion-inducing cysteine-rich protein with Kazal motifs


Mass: 106573.461 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RECK / Production host: Homo sapiens (human) / References: UniProt: O95980
#4: Chemical ChemComp-PAM / PALMITOLEIC ACID


Mass: 254.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H30O2 / Feature type: SUBJECT OF INVESTIGATION
#5: 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
Has ligand of interestY

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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-RECK Complex / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
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

CTF correctionType: NONE
3D reconstructionResolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87543 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037104
ELECTRON MICROSCOPYf_angle_d0.5899595
ELECTRON MICROSCOPYf_dihedral_angle_d6.868963
ELECTRON MICROSCOPYf_chiral_restr0.0411031
ELECTRON MICROSCOPYf_plane_restr0.0061207

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