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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 / positive regulation of timing of anagen / negative regulation of cell proliferation in midbrain / primary heart field specification / chemorepulsion of dopaminergic neuron axon / postsynapse assembly / olfactory bulb interneuron development / positive regulation of protein kinase C activity ...optic cup formation involved in camera-type eye development / receptor tyrosine kinase-like orphan receptor binding / chemoattraction of serotonergic neuron axon / positive regulation of timing of anagen / negative regulation of cell proliferation in midbrain / primary heart field specification / chemorepulsion of dopaminergic neuron axon / postsynapse assembly / olfactory bulb interneuron development / positive regulation of protein kinase C activity / chemoattractant activity involved in axon guidance / melanocyte proliferation / negative regulation of mesenchymal cell proliferation / negative regulation of melanin biosynthetic process / Wnt signaling pathway, calcium modulating pathway / regulation of postsynaptic cytosolic calcium ion concentration / Wnt protein secretion / cementum mineralization / negative regulation of synapse assembly / macrophage derived foam cell differentiation / atrial septum development / positive regulation of Wnt protein secretion / secondary heart field specification / positive regulation of non-canonical Wnt signaling pathway / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / WNT5A-dependent internalization of FZD2, FZD5 and ROR2 / WNT ligand biogenesis and trafficking / excitatory synapse assembly / anterior/posterior axis specification, embryo / embryonic skeletal system development / WNT5A-dependent internalization of FZD4 / positive regulation of macrophage cytokine production / face development / anterior/posterior axis specification / secondary palate development / exocrine pancreas development / positive regulation of neuron projection arborization / presynapse assembly / hindbrain development / positive regulation of T cell chemotaxis / genitalia development / ventricular septum development / non-canonical Wnt signaling pathway / Wnt-protein binding / WNT5:FZD7-mediated leishmania damping / lens development in camera-type eye / positive regulation of cytokine production involved in immune response / hematopoietic stem cell proliferation / positive regulation of response to cytokine stimulus / midbrain dopaminergic neuron differentiation / cartilage development / positive regulation of macrophage activation / mesoderm formation / positive regulation of ossification / positive regulation of type I interferon-mediated signaling pathway / PCP/CE pathway / Class B/2 (Secretin family receptors) / frizzled binding / regulation of postsynapse organization / inhibitory synapse assembly / Wnt signaling pathway, planar cell polarity pathway / regulation of canonical NF-kappaB signal transduction / negative regulation of fat cell differentiation / midbrain development / positive regulation of Rac protein signal transduction / positive regulation of protein localization to synapse / cell fate commitment / regulation of synapse organization / canonical Wnt signaling pathway / keratinocyte differentiation / epithelial to mesenchymal transition / cellular response to transforming growth factor beta stimulus / positive regulation of Wnt signaling pathway / postsynaptic modulation of chemical synaptic transmission / cellular response to retinoic acid / positive regulation of chemokine production / positive regulation of endothelial cell proliferation / endomembrane system / male gonad development / cellular response to calcium ion / positive regulation of apoptotic signaling pathway / positive regulation of endothelial cell migration / Wnt signaling pathway / axon guidance / positive regulation of fibroblast proliferation / cytokine activity / wound healing / positive regulation of interleukin-8 production / positive regulation of interleukin-1 beta production / positive regulation of neuron projection development / TCF dependent signaling in response to WNT / trans-Golgi network / clathrin-coated endocytic vesicle membrane / negative regulation of canonical Wnt signaling pathway / intracellular protein transport / Asymmetric localization of PCP proteins / cellular response to type II interferon / positive regulation of type II interferon production / phospholipid binding / positive regulation of interleukin-6 production
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-
UpdateAug 19, 2026-
Current statusAug 19, 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

Projections

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

Projections

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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