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- PDB-9z67: Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Composite map -

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Basic information

Entry
Database: PDB / ID: 9z67
TitleCryo-EM structure of human Wntless-Wnt5a 2:2 complex - Composite map
Components
  • Protein Wnt-5a
  • Protein wntless homolog
KeywordsMEMBRANE PROTEIN / Wnt transporter / Wnt secretion / Wnt5a / Wnt signaling
Function / homology
Function and homology information


optic cup formation involved in camera-type eye development / receptor tyrosine kinase-like orphan receptor binding / chemoattraction of serotonergic neuron axon / hypophysis morphogenesis / positive regulation of timing of anagen / cervix development / negative regulation of cell proliferation in midbrain / primary heart field specification / chemorepulsion of dopaminergic neuron axon / notochord morphogenesis ...optic cup formation involved in camera-type eye development / receptor tyrosine kinase-like orphan receptor binding / chemoattraction of serotonergic neuron axon / hypophysis morphogenesis / positive regulation of timing of anagen / cervix development / negative regulation of cell proliferation in midbrain / primary heart field specification / chemorepulsion of dopaminergic neuron axon / notochord morphogenesis / regulation of branching involved in mammary gland duct morphogenesis / mesodermal to mesenchymal transition involved in gastrulation / negative regulation of prostatic bud formation / postsynapse assembly / olfactory bulb interneuron development / positive regulation of protein kinase C activity / chemoattractant activity involved in axon guidance / mammary gland branching involved in thelarche / melanocyte proliferation / convergent extension involved in axis elongation / convergent extension involved in organogenesis / lateral sprouting involved in mammary gland duct morphogenesis / mesenchymal-epithelial cell signaling / negative regulation of mesenchymal cell proliferation / negative regulation of melanin biosynthetic process / paraxial mesoderm formation / meiotic nuclear division / Wnt signaling pathway, calcium modulating pathway / regulation of postsynaptic cytosolic calcium ion concentration / hindgut morphogenesis / positive regulation of hematopoietic stem cell proliferation / mesenchymal cell proliferation / urinary bladder development / negative regulation of axon extension involved in axon guidance / Wnt protein secretion / negative regulation of synapse assembly / epithelial cell migration / cochlea morphogenesis / establishment of planar polarity / macrophage derived foam cell differentiation / positive regulation of Wnt protein secretion / positive regulation of non-canonical Wnt signaling pathway / pericardium morphogenesis / positive regulation of cell-cell adhesion mediated by cadherin / secondary heart field specification / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / negative regulation of fibroblast growth factor receptor signaling pathway / primitive streak formation / WNT ligand biogenesis and trafficking / positive regulation of cartilage development / WNT5A-dependent internalization of FZD2, FZD5 and ROR2 / excitatory synapse assembly / anterior/posterior axis specification, embryo / axon extension involved in axon guidance / midgut development / WNT5A-dependent internalization of FZD4 / embryonic skeletal system development / cementum mineralization / secondary palate development / type B pancreatic cell development / positive regulation of neuron projection arborization / presynapse assembly / positive regulation of meiotic nuclear division / hindbrain development / positive regulation of T cell chemotaxis / genitalia development / non-canonical Wnt signaling pathway / exocrine pancreas development / post-anal tail morphogenesis / positive regulation of macrophage cytokine production / Wnt-protein binding / positive regulation of cytokine production involved in immune response / positive regulation of mesenchymal cell proliferation / atrial septum development / WNT5:FZD7-mediated leishmania damping / lens development in camera-type eye / positive regulation of response to cytokine stimulus / establishment of epithelial cell apical/basal polarity / midbrain dopaminergic neuron differentiation / ventricular septum development / positive regulation of macrophage activation / anterior/posterior axis specification / frizzled binding / positive regulation of type I interferon-mediated signaling pathway / positive regulation of ossification / cartilage development / PCP/CE pathway / thymocyte apoptotic process / Class B/2 (Secretin family receptors) / positive regulation of thymocyte apoptotic process / embryonic digit morphogenesis / hematopoietic stem cell proliferation / inhibitory synapse assembly / regulation of postsynapse organization / regulation of canonical NF-kappaB signal transduction / Wnt signaling pathway, planar cell polarity pathway / negative regulation of fat cell differentiation / face development / epithelial cell proliferation involved in mammary gland duct elongation / midbrain development
Similarity search - Function
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
Similarity search - Domain/homology
CHOLESTEROL / PALMITOLEIC ACID / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Protein Wnt-5a / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.32 Å
AuthorsGe, Y. / de Almeida Magalhaes, T. / Wu, H. / Yadav, G.P. / Wang, Z. / Salic, A. / Jiang, J. / Huang, P.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM150878 United States
CitationJournal: Nat Commun / Year: 2026
Title: Conformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens.
Authors: Yunhui Ge / Taciani de Almeida Magalhaes / Hongjiang Wu / Dick J H van den Boomen / Thu Uyen Nguyen / Tongyi Dou / Gaya P Yadav / Sukyeong Lee / Zhao Wang / Andrew Lemoff / Xuemei Luo / ...Authors: Yunhui Ge / Taciani de Almeida Magalhaes / Hongjiang Wu / Dick J H van den Boomen / Thu Uyen Nguyen / Tongyi Dou / Gaya P Yadav / Sukyeong Lee / Zhao Wang / Andrew Lemoff / Xuemei Luo / Sumitha S Menon / Min Zhang / Jin Wang / Zhicheng Jin / Jiansen Jiang / Adrian Salic / Pengxiang Huang /
Abstract: Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts ...Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts from the endoplasmic reticulum to the plasma membrane, then transfers them to extracellular carriers, forming active and soluble morphogen-carrier complexes. To dissect the mechanisms involved, we solve cryo-EM structures of Wnt-bound WLS and unliganded WLS, and perform structure-guided functional experiments. Wnts engage WLS via three conserved hairpins, which are all required for Wnt trafficking to the cell surface and carrier-mediated secretion. Wnt release from cells is driven by dramatic conformational changes in the WLS transmembrane domain, reminiscent of GPCR activation, together with WLS extracellular rearrangements. Unexpectedly, we find that Wnt5a bound to WLS forms dimers, with implications for Wnt signaling. These findings define the mechanism of WLS conformational cycling that governs the intracellular transport and extracellular release of Wnt morphogens, essential steps in the Wnt pathway.
History
DepositionNov 13, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 10, 2026Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jun 10, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.1Jul 1, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Protein Wnt-5a
B: Protein wntless homolog
C: Protein Wnt-5a
D: Protein wntless homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)214,43116
Polymers209,8414
Non-polymers4,59012
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

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Protein , 2 types, 4 molecules ACBD

#1: Protein Protein Wnt-5a


Mass: 38832.180 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WNT5A / Production host: Homo sapiens (human) / References: UniProt: P41221
#2: Protein Protein wntless homolog / Integral membrane protein GPR177 / Protein evenness interrupted homolog / EVI / Putative NF-kappa-B- ...Integral membrane protein GPR177 / Protein evenness interrupted homolog / EVI / Putative NF-kappa-B-activating protein 373


Mass: 66088.141 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WLS, C1orf139, GPR177, UNQ85/PRO18667 / Production host: Homo sapiens (human) / References: UniProt: Q5T9L3

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Sugars , 2 types, 6 molecules

#3: 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.: 2
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
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

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Non-polymers , 3 types, 6 molecules

#4: Chemical ChemComp-PAM / PALMITOLEIC ACID


Mass: 254.408 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H30O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-PCW / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / (Z,Z)-4-HYDROXY-N,N,N-TRIMETHYL-10-OXO-7-[(1-OXO-9-OCTADECENYL)OXY]-3,5,9-TRIOXA-4-PHOSPHAHEPTACOS-18-EN-1-AMINIUM-4-OXIDE


Mass: 787.121 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H85NO8P / Comment: DOPC, 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: human Wntless-Wnt5a 2:2 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50.83 e/Å2 / Film or detector model: GATAN K3 BIOCONTINUUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topazparticle selection
2PHENIX1.20_4459:model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.32 Å / Resolution method: OTHER / Num. of particles: 174062 / Symmetry type: POINT
RefinementCross valid method: NONE

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