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- EMDB-30827: Human Wntless in complex with Wnt3a -

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Basic information

Entry
Database: EMDB / ID: EMD-30827
TitleHuman Wntless in complex with Wnt3a
Map data2.2_angstrom_map for WLS-Wnt3a complex
Sample
  • Complex: Human Wntless in complex with Wnt3a
    • Complex: Wnt3a
      • Protein or peptide: Protein Wnt-3a
    • Complex: Wntless
      • Protein or peptide: Protein wntless homolog
  • Ligand: PALMITOLEIC ACID
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: water
Function / homology
Function and homology information


Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / : / positive regulation of collateral sprouting in absence of injury / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / Specification of the neural plate border / cell proliferation in midbrain ...Wnt signaling pathway involved in forebrain neuroblast division / positive regulation of dermatome development / axis elongation involved in somitogenesis / calcium ion transmembrane transport via low voltage-gated calcium channel / : / positive regulation of collateral sprouting in absence of injury / positive regulation of mesodermal cell fate specification / paraxial mesodermal cell fate commitment / Specification of the neural plate border / cell proliferation in midbrain / spinal cord association neuron differentiation / Formation of the posterior neural plate / Wnt protein secretion / COP9 signalosome assembly / Wnt-Frizzled-LRP5/6 complex / positive regulation of cell-cell adhesion mediated by cadherin / positive regulation of Wnt protein secretion / Negative regulation of TCF-dependent signaling by WNT ligand antagonists / synaptic vesicle recycling / Signaling by RNF43 mutants / WNT ligand biogenesis and trafficking / positive regulation of cardiac muscle cell differentiation / cell proliferation in forebrain / secondary palate development / negative regulation of axon extension involved in axon guidance / cementum mineralization / somatic stem cell division / non-canonical Wnt signaling pathway / co-receptor binding / cardiac muscle cell fate commitment / presynapse assembly / hindbrain development / positive regulation of skeletal muscle tissue development / dorsal/ventral neural tube patterning / negative regulation of dopaminergic neuron differentiation / Wnt-protein binding / midbrain dopaminergic neuron differentiation / regulation of postsynapse to nucleus signaling pathway / post-anal tail morphogenesis / exocrine pancreas development / mammary gland development / positive regulation of neural precursor cell proliferation / frizzled binding / positive regulation of hepatocyte proliferation / Class B/2 (Secretin family receptors) / myoblast differentiation / Disassembly of the destruction complex and recruitment of AXIN to the membrane / anterior/posterior axis specification / inner ear morphogenesis / midbrain development / regulation of synapse organization / negative regulation of fat cell differentiation / fat cell differentiation / heart looping / B cell proliferation / Formation of paraxial mesoderm / skeletal muscle cell differentiation / positive regulation of receptor internalization / hemopoiesis / regulation of presynapse assembly / mesoderm formation / positive regulation of Wnt signaling pathway / canonical Wnt signaling pathway / cell fate commitment / endomembrane system / regulation of microtubule cytoskeleton organization / cellular response to retinoic acid / positive regulation of B cell proliferation / Regulation of FZD by ubiquitination / extracellular matrix organization / TCF dependent signaling in response to WNT / positive regulation of cytokine production / cytokine activity / hippocampus development / positive regulation of protein localization to plasma membrane / axon guidance / intracellular protein transport / modulation of chemical synaptic transmission / trans-Golgi network / neuron differentiation / protein localization / platelet aggregation / Wnt signaling pathway / negative regulation of neurogenesis / Golgi lumen / osteoblast differentiation / endocytic vesicle membrane / positive regulation of canonical Wnt signaling pathway / presynapse / positive regulation of peptidyl-serine phosphorylation / negative regulation of neuron projection development / heart development / early endosome membrane / cytoplasmic vesicle / positive regulation of canonical NF-kappaB signal transduction / in utero embryonic development / cell population proliferation / transcription by RNA polymerase II / transcription coactivator activity / receptor ligand activity
Similarity search - Function
Wnt-3 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
Similarity search - Domain/homology
Protein Wnt-3a / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsZhong Q / Zhao Y / Ye F / Xiao Z / Huang G / Zhang Y / Lu P / Xu W / Zhou Q / Ma D
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31971123 China
CitationJournal: Nat Commun / Year: 2021
Title: Cryo-EM structure of human Wntless in complex with Wnt3a.
Authors: Qing Zhong / Yanyu Zhao / Fangfei Ye / Zaiyu Xiao / Gaoxingyu Huang / Meng Xu / Yuanyuan Zhang / Xiechao Zhan / Ke Sun / Zhizhi Wang / Shanshan Cheng / Shan Feng / Xiuxiu Zhao / Jizhong ...Authors: Qing Zhong / Yanyu Zhao / Fangfei Ye / Zaiyu Xiao / Gaoxingyu Huang / Meng Xu / Yuanyuan Zhang / Xiechao Zhan / Ke Sun / Zhizhi Wang / Shanshan Cheng / Shan Feng / Xiuxiu Zhao / Jizhong Zhang / Peilong Lu / Wenqing Xu / Qiang Zhou / Dan Ma /
Abstract: Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas ...Wntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.
History
DepositionDec 29, 2020-
Header (metadata) releaseJul 14, 2021-
Map releaseJul 14, 2021-
UpdateSep 8, 2021-
Current statusSep 8, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.25
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.25
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7drt
  • Surface level: 0.25
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30827.png

Downloads & links

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Map

FileDownload / File: emd_30827.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotation2.2_angstrom_map for WLS-Wnt3a complex
Voxel sizeX=Y=Z: 0.5435 Å
Density
Contour LevelBy AUTHOR: 0.2 / Movie #1: 0.25
Minimum - Maximum-4.23394 - 9.254435
Average (Standard dev.)-0.00030710245 (±0.05671689)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 278.272 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.54350.54350.5435
M x/y/z512512512
origin x/y/z0.0000.0000.000
length x/y/z278.272278.272278.272
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS512512512
D min/max/mean-4.2349.254-0.000

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Supplemental data

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Additional map: 3.2 angstrom map for WLS-Wnt3a complex

Fileemd_30827_additional_1.map
Annotation3.2_angstrom_map for WLS-Wnt3a complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human Wntless in complex with Wnt3a

EntireName: Human Wntless in complex with Wnt3a
Components
  • Complex: Human Wntless in complex with Wnt3a
    • Complex: Wnt3a
      • Protein or peptide: Protein Wnt-3a
    • Complex: Wntless
      • Protein or peptide: Protein wntless homolog
  • Ligand: PALMITOLEIC ACID
  • Ligand: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: CHOLESTEROL
  • Ligand: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: water

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Supramolecule #1: Human Wntless in complex with Wnt3a

SupramoleculeName: Human Wntless in complex with Wnt3a / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Supramolecule #2: Wnt3a

SupramoleculeName: Wnt3a / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293

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Supramolecule #3: Wntless

SupramoleculeName: Wntless / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Protein Wnt-3a

MacromoleculeName: Protein Wnt-3a / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.421832 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAPLGYFLLL CSLKQALGSY PIWWSLAVGP QYSSLGSQPI LCASIPGLVP KQLRFCRNYV EIMPSVAEGI KIGIQECQHQ FRGRRWNCT TVHDSLAIFG PVLDKATRES AFVHAIASAG VAFAVTRSCA EGTAAICGCS SRHQGSPGKG WKWGGCSEDI E FGGMVSRE ...String:
MAPLGYFLLL CSLKQALGSY PIWWSLAVGP QYSSLGSQPI LCASIPGLVP KQLRFCRNYV EIMPSVAEGI KIGIQECQHQ FRGRRWNCT TVHDSLAIFG PVLDKATRES AFVHAIASAG VAFAVTRSCA EGTAAICGCS SRHQGSPGKG WKWGGCSEDI E FGGMVSRE FADARENRPD ARSAMNRHNN EAGRQAIASH MHLKCKCHGL SGSCEVKTCW WSQPDFRAIG DFLKDKYDSA SE MVVEKHR ESRGWVETLR PRYTYFKVPT ERDLVYYEAS PNFCEPNPET GSFGTRDRTC NVSSHGIDGC DLLCCGRGHN ARA ERRREK CRCVFHWCCY VSCQECTRVY DVHTCK

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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: 62.317973 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 TRKEAQE

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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 / Palmitoleic acid

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Macromolecule #5: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 5 / Number of copies: 2 / 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 #6: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 6 / Number of copies: 1 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL / Cholesterol

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Macromolecule #7: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 7 / 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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Macromolecule #8: water

MacromoleculeName: water / type: ligand / ID: 8 / Number of copies: 10 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER / Water

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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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0.6) / Number images used: 8482332

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