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- PDB-7drt: Human Wntless in complex with Wnt3a -

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Basic information

Entry
Database: PDB / ID: 7drt
TitleHuman Wntless in complex with Wnt3a
Components
  • Protein Wnt-3a
  • Protein wntless homolog
KeywordsMEMBRANE PROTEIN / Wnt signaling / Wnt secretion / WLS / Wnt3a / cryo-EM / palmitoleoylation
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 / cell proliferation in midbrain / spinal cord association neuron differentiation ...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 / 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 / Wnt-protein binding / dorsal/ventral neural tube patterning / negative regulation of dopaminergic neuron differentiation / 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 / negative regulation of fat cell differentiation / midbrain development / regulation of synapse organization / 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 / endomembrane system / cell fate commitment / 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 / cytokine activity / axon guidance / positive regulation of cytokine production / hippocampus development / positive regulation of protein localization to plasma membrane / intracellular protein transport / modulation of chemical synaptic transmission / trans-Golgi network / protein localization / neuron differentiation / platelet aggregation / Wnt signaling pathway / osteoblast differentiation / negative regulation of neurogenesis / Golgi lumen / positive regulation of canonical Wnt signaling pathway / endocytic vesicle membrane / presynapse / negative regulation of neuron projection development / positive regulation of peptidyl-serine phosphorylation / heart development / cytoplasmic vesicle / early endosome membrane / 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 / early endosome
Similarity search - Function
Wnt-3 protein / Protein wntless / : / Wnt-binding factor required for Wnt secretion / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family / found in Wnt-1
Similarity search - Domain/homology
CHOLESTEROL / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / PALMITOLEIC ACID / 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Protein Wnt-3a / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single 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, 1items
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, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 14, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 8, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _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 / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Protein Wnt-3a
B: Protein wntless homolog
hetero molecules


Theoretical massNumber of molelcules
Total (without water)104,8908
Polymers101,7402
Non-polymers3,1506
Water18010
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area10720 Å2
ΔGint-50 kcal/mol
Surface area42270 Å2

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Protein Wnt-3a


Mass: 39421.832 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WNT3A / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P56704
#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: 62317.973 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WLS, C1orf139, GPR177, UNQ85/PRO18667 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q5T9L3

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Sugars , 1 types, 1 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.: 1 / Source method: obtained synthetically
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

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Non-polymers , 5 types, 15 molecules

#4: Chemical ChemComp-PAM / PALMITOLEIC ACID / Palmitoleic acid


Mass: 254.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H30O2
#5: 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
#6: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-LPE / 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE / LPC-ETHER


Mass: 510.708 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H57NO6P
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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

Component
IDNameTypeEntity IDParent-IDSource
1Human Wntless in complex with Wnt3aCOMPLEX#1-#20RECOMBINANT
2Wnt3aCOMPLEX#11RECOMBINANT
3WntlessCOMPLEX#21RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Homo sapiens (human)9606HEK293
32Homo sapiens (human)9606HEK293
Buffer solutionpH: 8
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 FIELDBright-field microscopy / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: RELION / Version: 3.0.6 / Category: 3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 8482332 / Symmetry type: POINT

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