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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


Wnt protein secretion / Calnexin/calreticulin cycle / cytolytic granule / positive regulation of Wnt protein secretion / WNT ligand biogenesis and trafficking / positive regulation of dendritic cell chemotaxis / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / negative regulation of trophoblast cell migration / cortical granule ...Wnt protein secretion / Calnexin/calreticulin cycle / cytolytic granule / positive regulation of Wnt protein secretion / WNT ligand biogenesis and trafficking / positive regulation of dendritic cell chemotaxis / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / negative regulation of trophoblast cell migration / cortical granule / cellular response to electrical stimulus / nuclear receptor-mediated glucocorticoid signaling pathway / complement component C1q complex binding / regulation of meiotic nuclear division / negative regulation of retinoic acid receptor signaling pathway / cementum mineralization / response to glycoside / endoplasmic reticulum quality control compartment / sequestering of calcium ion / sarcoplasmic reticulum lumen / protein folding in endoplasmic reticulum / hormone binding / hindbrain development / negative regulation of intracellular steroid hormone receptor signaling pathway / Wnt-protein binding / nuclear export signal receptor activity / cardiac muscle cell differentiation / exocrine pancreas development / molecular sequestering activity / anterior/posterior axis specification / Scavenging by Class A Receptors / protein maturation by protein folding / Scavenging by Class F Receptors / midbrain development / cortical actin cytoskeleton organization / nuclear androgen receptor binding / cellular response to lithium ion / organelle membrane / response to testosterone / positive regulation of Wnt signaling pathway / mesoderm formation / protein localization to nucleus / negative regulation of neuron differentiation / smooth endoplasmic reticulum / endomembrane system / positive regulation of cell cycle / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / ERAD pathway / endocytic vesicle lumen / protein folding chaperone / endoplasmic reticulum-Golgi intermediate compartment membrane / protein export from nucleus / positive regulation of endothelial cell migration / acrosomal vesicle / intracellular protein transport / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / peptide binding / trans-Golgi network / peptide antigen assembly with MHC class I protein complex / MHC class I peptide loading complex / cellular response to virus / Wnt signaling pathway / intracellular calcium ion homeostasis / positive regulation of non-canonical NF-kappaB signal transduction / phagocytic vesicle membrane / cellular senescence / endocytic vesicle membrane / positive regulation of canonical Wnt signaling pathway / unfolded protein binding / integrin binding / protein folding / response to estradiol / nuclear envelope / protein-folding chaperone binding / ER-Phagosome pathway / early endosome membrane / cytoplasmic vesicle / spermatogenesis / carbohydrate binding / collagen-containing extracellular matrix / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / early endosome / negative regulation of translation / protein stabilization / ribosome / iron ion binding / response to xenobiotic stimulus / endoplasmic reticulum lumen / Golgi membrane / external side of plasma membrane / focal adhesion / negative regulation of DNA-templated transcription / mRNA binding / ubiquitin protein ligase binding / calcium ion binding / positive regulation of cell population proliferation / endoplasmic reticulum membrane
Similarity search - Function
Protein wntless / : / Wntless-like, transmembrane domain / Calreticulin / Calreticulin family repeated motif signature. / Calreticulin/calnexin / Calreticulin/calnexin, P domain superfamily / Calreticulin/calnexin, conserved site / Calreticulin family / Calreticulin family signature 1. ...Protein wntless / : / Wntless-like, transmembrane domain / 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
: / 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)

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: 0.514
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 (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: UNIPROTKB: O00755

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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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