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- EMDB-73803: Cryo-EM structure of human Wntless in complex with Wnt5a at 1:1 s... -

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Entry
Database: EMDB / ID: EMD-73803
TitleCryo-EM structure of human Wntless in complex with Wnt5a at 1:1 stoichiometry
Map datastructure of human Wntless in complex with Wnt5a at 1:1 stoichiometry
Sample
  • Complex: human Wntless in complex with Wnt5a at 1:1 stoichiometry
    • Protein or peptide: Protein Wnt-5a
    • Protein or peptide: Protein wntless homolog
  • Ligand: PALMITOLEIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
KeywordsWnt transporter / Wnt5a / Wnt signaling / MEMBRANE PROTEIN
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
Protein Wnt-5a / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.64 Å
AuthorsGe Y / de Almeida Magalhaes T / Wu H / Wang Z / Salic A / Jiang J / Huang P
Funding support United States, 1 items
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 10, 2025-
Header (metadata) releaseJun 10, 2026-
Map releaseJun 10, 2026-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_73803.png

Downloads & links

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Map

FileDownload / File: emd_73803.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationstructure of human Wntless in complex with Wnt5a at 1:1 stoichiometry
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å		0.83 Å/pix.
x 320 pix.
= 265.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.164
Minimum - Maximum-1.3030255 - 1.8802546
Average (Standard dev.)0.0010689353 (±0.026431495)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 265.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_73803_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Half Map A

Fileemd_73803_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_73803_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : human Wntless in complex with Wnt5a at 1:1 stoichiometry

EntireName: human Wntless in complex with Wnt5a at 1:1 stoichiometry
Components
  • Complex: human Wntless in complex with Wnt5a at 1:1 stoichiometry
    • Protein or peptide: Protein Wnt-5a
    • Protein or peptide: Protein wntless homolog
  • Ligand: PALMITOLEIC ACID
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Supramolecule #1: human Wntless in complex with Wnt5a at 1:1 stoichiometry

SupramoleculeName: human Wntless in complex with Wnt5a at 1:1 stoichiometry
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein Wnt-5a

MacromoleculeName: Protein Wnt-5a / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.913203 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: FAQVVIEANS WWSLGMNNPV QMSEVYIIGA QPLCSQLAGL SQGQKKLCHL YQDHMQYIGE GAKTGIKECQ YQFRHRRWNC STVDNTSVF GRVMQIGSRE TAFTYAVSAA GVVNAMSRAC REGELSTCGC SRAARPKDLP RDWLWGGCGD NIDYGYRFAK E FVDARERE ...String:
FAQVVIEANS WWSLGMNNPV QMSEVYIIGA QPLCSQLAGL SQGQKKLCHL YQDHMQYIGE GAKTGIKECQ YQFRHRRWNC STVDNTSVF GRVMQIGSRE TAFTYAVSAA GVVNAMSRAC REGELSTCGC SRAARPKDLP RDWLWGGCGD NIDYGYRFAK E FVDARERE RIHAKGSYES ARILMNLHNN EAGRRTVYNL ADVACKCHGV SGSCSLKTCW LQLADFRKVG DALKEKYDSA AA MRLNSRG KLVQVNSRFN SPTTQDLVYI DPSPDYCVRN ESTGSLGTQG RLCNKTSEGM DGCELMCCGR GYDQFKTVQT ERC HCKFHW CCYVKCKKCT EIVDQFVCKA ADYKDDDDA

UniProtKB: Protein Wnt-5a

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Macromolecule #2: Protein wntless homolog

MacromoleculeName: Protein wntless homolog / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.088141 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAGAIIENMS TKKLCIVGGI LLVFQIIAFL VGGLIAPGPT TAVSYMSVKC VDARKNHHKT KWFVPWGPNH CDKIRDIEEA IPREIEAND IVFSVHIPLP HMEMSPWFQF MLFILQLDIA FKLNNQIREN AEVSMDVSLA YRDDAFAEWT EMAHERVPRK L KCTFTSPK ...String:
MAGAIIENMS TKKLCIVGGI LLVFQIIAFL VGGLIAPGPT TAVSYMSVKC VDARKNHHKT KWFVPWGPNH CDKIRDIEEA IPREIEAND IVFSVHIPLP HMEMSPWFQF MLFILQLDIA FKLNNQIREN AEVSMDVSLA YRDDAFAEWT EMAHERVPRK L KCTFTSPK TPEHEGRYYE CDVLPFMEIG SVAHKFYLLN IRLPVNEKKK INVGIGEIKD IRLVGIHQNG GFTKVWFAMK TF LTPSIFI IMVWYWRRIT MMSRPPVLLE KVIFALGISM TFINIPVEWF SIGFDWTWML LFGDIRQGIF YAMLLSFWII FCG EHMMDQ HERNHIAGYW KQVGPIAVGS FCLFIFDMCE RGVQLTNPFY SIWTTDIGTE LAMAFIIVAG ICLCLYFLFL CFMV FQVFR NISGKQSSLP AMSKVRRLHY EGLIFRFKFL MLITLACAAM TVIFFIVSQV TEGHWKWGGV TVQVNSAFFT GIYGM WNLY VFALMFLYAP SHKNYGEDQS NGDLGVHSGE ELQLTTTITH VDGPTEIYKL TRKEAQEAAA LEVLFQGPGA AEDQVD PRL IDGKHHHHHH HH

UniProtKB: Protein wntless homolog

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Macromolecule #4: PALMITOLEIC ACID

MacromoleculeName: PALMITOLEIC ACID / type: ligand / ID: 4 / Number of copies: 1 / Formula: PAM
Molecular weightTheoretical: 254.408 Da
Chemical component information

ChemComp-PAM:
PALMITOLEIC ACID

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #6: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 6 / Number of copies: 5 / Formula: PCW
Molecular weightTheoretical: 787.121 Da
Chemical component information

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #8: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 8 / Number of copies: 1 / Formula: LPE
Molecular weightTheoretical: 510.708 Da
Chemical component information

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.64 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 104884
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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