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- EMDB-41764: Structure of human Wnt7a bound to WLS and CALR -

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Basic information

Entry
Database: EMDB / ID: EMD-41764
TitleStructure of human Wnt7a bound to WLS and CALR
Map data
Sample
  • Complex: Wnt7a-WLS-CALR Complex
    • Protein or peptide: Protein Wnt-7a
    • Protein or peptide: Protein wntless homolog
    • Protein or peptide: Calreticulin
  • Ligand: PALMITOLEIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CALCIUM ION
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


regulation of axon diameter / postsynapse assembly / positive regulation of excitatory synapse assembly / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / Calnexin/calreticulin cycle / asymmetric protein localization involved in cell fate determination / excitatory synapse assembly / cerebellar granule cell differentiation ...regulation of axon diameter / postsynapse assembly / positive regulation of excitatory synapse assembly / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / Calnexin/calreticulin cycle / asymmetric protein localization involved in cell fate determination / excitatory synapse assembly / cerebellar granule cell differentiation / cytolytic granule / lens fiber cell development / positive regulation of Wnt protein secretion / positive regulation of dendritic cell chemotaxis / synaptic vesicle recycling / WNT ligand biogenesis and trafficking / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / oviduct development / negative regulation of trophoblast cell migration / cortical granule / central nervous system vasculogenesis / cell proliferation in forebrain / nuclear receptor-mediated glucocorticoid signaling pathway / cellular response to electrical stimulus / complement component C1q complex binding / regulation of meiotic nuclear division / uterus morphogenesis / negative regulation of retinoic acid receptor signaling pathway / embryonic axis specification / secondary palate development / response to glycoside / endoplasmic reticulum quality control compartment / cementum mineralization / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / sequestering of calcium ion / somatic stem cell division / sarcoplasmic reticulum lumen / protein folding in endoplasmic reticulum / hormone binding / presynapse assembly / sex differentiation / positive regulation of epithelial cell proliferation involved in wound healing / hindbrain development / negative regulation of intracellular steroid hormone receptor signaling pathway / stem cell development / Wnt-protein binding / nuclear export signal receptor activity / establishment of blood-brain barrier / cardiac muscle cell differentiation / exocrine pancreas development / neurotransmitter secretion / molecular sequestering activity / dendritic spine morphogenesis / frizzled binding / dorsal/ventral pattern formation / embryonic forelimb morphogenesis / embryonic hindlimb morphogenesis / positive regulation of synapse assembly / Class B/2 (Secretin family receptors) / wound healing, spreading of epidermal cells / anterior/posterior axis specification / Wnt signaling pathway, planar cell polarity pathway / Scavenging by Class A Receptors / Scavenging by Class F Receptors / protein maturation by protein folding / midbrain development / regulation of postsynapse organization / cortical actin cytoskeleton organization / regulation of synaptic vesicle exocytosis / cartilage condensation / embryonic digit morphogenesis / nuclear androgen receptor binding / establishment of cell polarity / cellular response to lithium ion / organelle membrane / response to testosterone / somatic stem cell population maintenance / positive regulation of Wnt signaling pathway / mesoderm formation / positive regulation of excitatory postsynaptic potential / protein localization to nucleus / regulation of presynapse assembly / negative regulation of neuron differentiation / cell fate commitment / endomembrane system / positive regulation of cell cycle / smooth endoplasmic reticulum / canonical Wnt signaling pathway / chondrocyte differentiation / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / cellular response to transforming growth factor beta stimulus / ERAD pathway / endocytic vesicle lumen / protein folding chaperone / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of protein metabolic process / protein export from nucleus / positive regulation of endothelial cell migration
Similarity search - Function
Wnt-7 protein / Protein wntless / : / : / Wntless-like, transmembrane domain / Wntless, GOLD domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain ...Wnt-7 protein / 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 / Calreticulin / Calreticulin family repeated motif signature. / Calreticulin/calnexin / Calreticulin/calnexin, P domain superfamily / Calreticulin/calnexin, conserved site / Calreticulin family / Calreticulin family signature 1. / Calreticulin family signature 2. / Endoplasmic reticulum targeting sequence. / Concanavalin A-like lectin/glucanase domain superfamily
Similarity search - Domain/homology
Protein Wnt-7a / Calreticulin / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsQi X / Hu Q / Li X
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM135343 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)HL160487 United States
Welch FoundationI-1957 United States
CitationJournal: Cell / Year: 2023
Title: Molecular basis of Wnt biogenesis, secretion, and Wnt7-specific signaling.
Authors: Xiaofeng Qi / Qinli Hu / Nadia Elghobashi-Meinhardt / Tao Long / Hongwen Chen / Xiaochun Li /
Abstract: Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility ...Wnt proteins are enzymatically lipidated by Porcupine (PORCN) in the ER and bind to Wntless (WLS) for intracellular transport and secretion. Mechanisms governing the transfer of these low-solubility Wnts from the ER to the extracellular space remain unclear. Through structural and functional analyses of Wnt7a, a crucial Wnt involved in central nervous system angiogenesis and blood-brain barrier maintenance, we have elucidated the principles of Wnt biogenesis and Wnt7-specific signaling. The Wnt7a-WLS complex binds to calreticulin (CALR), revealing that CALR functions as a chaperone to facilitate Wnt transfer from PORCN to WLS during Wnt biogenesis. Our structures, functional analyses, and molecular dynamics simulations demonstrate that a phospholipid in the core of Wnt-bound WLS regulates the association and dissociation between Wnt and WLS, suggesting a lipid-mediated Wnt secretion mechanism. Finally, the structure of Wnt7a bound to RECK, a cell-surface Wnt7 co-receptor, reveals how RECK engages the N-terminal domain of Wnt7a to activate Wnt7-specific signaling.
History
DepositionAug 27, 2023-
Header (metadata) releaseOct 18, 2023-
Map releaseOct 18, 2023-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41764.png

Downloads & links

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Map

FileDownload / File: emd_41764.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
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)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.514
Minimum - Maximum-2.668551 - 4.085847
Average (Standard dev.)0.003647782 (±0.07652284)
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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Half map: #2

Fileemd_41764_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_41764_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Wnt7a-WLS-CALR Complex

EntireName: Wnt7a-WLS-CALR Complex
Components
  • Complex: Wnt7a-WLS-CALR Complex
    • Protein or peptide: Protein Wnt-7a
    • Protein or peptide: Protein wntless homolog
    • Protein or peptide: Calreticulin
  • Ligand: PALMITOLEIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: CALCIUM ION

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Supramolecule #1: Wnt7a-WLS-CALR Complex

SupramoleculeName: Wnt7a-WLS-CALR Complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein Wnt-7a

MacromoleculeName: Protein Wnt-7a / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.062977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MNRKARRCLG HLFLSLGMVY LRIGGFSSVV ALGASIICNK IPGLAPRQRA ICQSRPDAII VIGEGSQMGL DECQFQFRNG RWNCSALGE RTVFGKELKV GSREAAFTYA IIAAGVAHAI TAACTQGNLS DCGCDKEKQG QYHRDEGWKW GGCSADIRYG I GFAKVFVD ...String:
MNRKARRCLG HLFLSLGMVY LRIGGFSSVV ALGASIICNK IPGLAPRQRA ICQSRPDAII VIGEGSQMGL DECQFQFRNG RWNCSALGE RTVFGKELKV GSREAAFTYA IIAAGVAHAI TAACTQGNLS DCGCDKEKQG QYHRDEGWKW GGCSADIRYG I GFAKVFVD AREIKQNART LMNLHNNEAG RKILEENMKL ECKCHGVSGS CTTKTCWTTL PQFRELGYVL KDKYNEAVHV EP VRASRNK RPTFLKIKKP LSYRKPMDTD LVYIEKSPNY CEEDPVTGSV GTQGRACNKT APQASGCDLM CCGRGYNTHQ YAR VWQCNC KFHWCCYVKC NTCSERTEMY TCK

UniProtKB: Protein Wnt-7a

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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

UniProtKB: Protein wntless homolog

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Macromolecule #3: Calreticulin

MacromoleculeName: Calreticulin / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 48.198379 KDa
SequenceString: MLLSVPLLLG LLGLAVAEPA VYFKEQFLDG DGWTSRWIES KHKSDFGKFV LSSGKFYGDE EKDKGLQTSQ DARFYALSAS FEPFSNKGQ TLVVQFTVKH EQNIDCGGGY VKLFPNSLDQ TDMHGDSEYN IMFGPDICGP GTKKVHVIFN YKGKNVLINK D IRCKDDEF ...String:
MLLSVPLLLG LLGLAVAEPA VYFKEQFLDG DGWTSRWIES KHKSDFGKFV LSSGKFYGDE EKDKGLQTSQ DARFYALSAS FEPFSNKGQ TLVVQFTVKH EQNIDCGGGY VKLFPNSLDQ TDMHGDSEYN IMFGPDICGP GTKKVHVIFN YKGKNVLINK D IRCKDDEF THLYTLIVRP DNTYEVKIDN SQVESGSLED DWDFLPPKKI KDPDASKPED WDERAKIDDP TDSKPEDWDK PE HIPDPDA KKPEDWDEEM DGEWEPPVIQ NPEYKGEWKP RQIDNPDYKG TWIHPEIDNP EYSPDPSIYA YDNFGVLGLD LWQ VKSGTI FDNFLITNDE AYAEEFGNET WGVTKAAEKQ MKDKQDEEQR LKEEEEDKKR KEEEEAEDKE DDEDKDEDEE DEED KEEDE EEDVPGQAKD EL

UniProtKB: Calreticulin

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Macromolecule #5: PALMITOLEIC ACID

MacromoleculeName: PALMITOLEIC ACID / type: ligand / ID: 5 / Number of copies: 1 / Formula: PAM
Molecular weightTheoretical: 254.408 Da
Chemical component information

ChemComp-PAM:
PALMITOLEIC ACID

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Macromolecule #6: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 6 / Number of copies: 1 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 276377
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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