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- EMDB-41765: Structure of human Wnt7a bound to WLS and RECK -

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Basic information

Entry
Database: EMDB / ID: EMD-41765
TitleStructure of human Wnt7a bound to WLS and RECK
Map data
Sample
  • Complex: Wnt7a-WLS-RECK Complex
    • Protein or peptide: Protein Wnt-7a
    • Protein or peptide: Protein wntless homolog
    • Protein or peptide: Reversion-inducing cysteine-rich protein with Kazal motifs
  • Ligand: PALMITOLEIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
KeywordsSIGNALING PROTEIN
Function / homology
Function and homology information


regulation of establishment of blood-brain barrier / : / postsynapse assembly / negative regulation of metalloendopeptidase activity / positive regulation of excitatory synapse assembly / regulation of axon diameter / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / asymmetric protein localization involved in cell fate determination ...regulation of establishment of blood-brain barrier / : / postsynapse assembly / negative regulation of metalloendopeptidase activity / positive regulation of excitatory synapse assembly / regulation of axon diameter / positive regulation of protein localization to presynapse / skeletal muscle satellite cell activation / Wnt protein secretion / asymmetric protein localization involved in cell fate determination / excitatory synapse assembly / cerebellar granule cell differentiation / blood vessel maturation / lens fiber cell development / positive regulation of Wnt protein secretion / synaptic vesicle recycling / WNT ligand biogenesis and trafficking / oviduct development / central nervous system vasculogenesis / cell proliferation in forebrain / uterus morphogenesis / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / secondary palate development / embryonic axis specification / Post-translational modification: synthesis of GPI-anchored proteins / cementum mineralization / metalloendopeptidase inhibitor activity / somatic stem cell division / presynapse assembly / sex differentiation / positive regulation of epithelial cell proliferation involved in wound healing / hindbrain development / stem cell development / Wnt-protein binding / establishment of blood-brain barrier / exocrine pancreas development / neurotransmitter secretion / dendritic spine morphogenesis / frizzled binding / dorsal/ventral pattern formation / embryonic forelimb morphogenesis / Wnt signalosome / Class B/2 (Secretin family receptors) / embryonic hindlimb morphogenesis / positive regulation of synapse assembly / wound healing, spreading of epidermal cells / sprouting angiogenesis / Wnt signaling pathway, planar cell polarity pathway / anterior/posterior axis specification / regulation of postsynapse organization / midbrain development / regulation of synaptic vesicle exocytosis / embryonic digit morphogenesis / cartilage condensation / endopeptidase inhibitor activity / establishment of cell polarity / somatic stem cell population maintenance / positive regulation of excitatory postsynaptic potential / regulation of presynapse assembly / mesoderm formation / positive regulation of Wnt signaling pathway / cell fate commitment / canonical Wnt signaling pathway / endomembrane system / regulation of angiogenesis / chondrocyte differentiation / side of membrane / cellular response to transforming growth factor beta stimulus / positive regulation of protein metabolic process / embryo implantation / positive regulation of endothelial cell migration / negative regulation of cell migration / extracellular matrix organization / axonogenesis / extracellular matrix / cytokine activity / positive regulation of JNK cascade / intracellular protein transport / Schaffer collateral - CA1 synapse / serine-type endopeptidase inhibitor activity / neuron differentiation / trans-Golgi network / Wnt signaling pathway / negative regulation of neurogenesis / Golgi lumen / response to estrogen / endocytic vesicle membrane / positive regulation of canonical Wnt signaling pathway / presynapse / response to estradiol / early endosome membrane / cytoplasmic vesicle / angiogenesis / positive regulation of canonical NF-kappaB signal transduction / receptor ligand activity / early endosome / endoplasmic reticulum lumen / Golgi membrane / signaling receptor binding / glutamatergic synapse
Similarity search - Function
Reversion-inducing cysteine-rich protein with Kazal motifs / Wnt-7 protein / Protein wntless / : / Wntless-like, transmembrane domain / Wnt protein, conserved site / Wnt-1 family signature. / Wnt / Wnt, C-terminal domain / wnt family ...Reversion-inducing cysteine-rich protein with Kazal motifs / Wnt-7 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 / Kazal-type serine protease inhibitor domain / Kazal serine protease inhibitors family signature. / Kazal type serine protease inhibitors / Kazal domain superfamily / Kazal domain / Kazal domain profile.
Similarity search - Domain/homology
Protein Wnt-7a / Reversion-inducing cysteine-rich protein with Kazal motifs / Protein wntless homolog
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.23 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-
UpdateMay 8, 2024-
Current statusMay 8, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41765.png

Downloads & links

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Map

FileDownload / File: emd_41765.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.418
Minimum - Maximum-1.9154313 - 2.9754672
Average (Standard dev.)0.0020350334 (±0.057605032)
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: #1

Fileemd_41765_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_41765_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Wnt7a-WLS-RECK Complex

EntireName: Wnt7a-WLS-RECK Complex
Components
  • Complex: Wnt7a-WLS-RECK Complex
    • Protein or peptide: Protein Wnt-7a
    • Protein or peptide: Protein wntless homolog
    • Protein or peptide: Reversion-inducing cysteine-rich protein with Kazal motifs
  • Ligand: PALMITOLEIC ACID
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate

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Supramolecule #1: Wnt7a-WLS-RECK Complex

SupramoleculeName: Wnt7a-WLS-RECK 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: Reversion-inducing cysteine-rich protein with Kazal motifs

MacromoleculeName: Reversion-inducing cysteine-rich protein with Kazal motifs
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106.573461 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATVRASLRG ALLLLLAVAG VAEVAGGLAP GSAGALCCNH SKDNQMCRDV CEQIFSSKSE SRLKHLLQRA PDYCPETMVE IWNCMNSSL PGVFKKSDGW VGLGCCELAI ALECRQACKQ ASSKNDISKV CRKEYENALF SCISRNEMGS VCCSYAGHHT N CREYCQAI ...String:
MATVRASLRG ALLLLLAVAG VAEVAGGLAP GSAGALCCNH SKDNQMCRDV CEQIFSSKSE SRLKHLLQRA PDYCPETMVE IWNCMNSSL PGVFKKSDGW VGLGCCELAI ALECRQACKQ ASSKNDISKV CRKEYENALF SCISRNEMGS VCCSYAGHHT N CREYCQAI FRTDSSPGPS QIKAVENYCA SISPQLIHCV NNYTQSYPMR NPTDSLYCCD RAEDHACQNA CKRILMSKKT EM EIVDGLI EGCKTQPLPQ DPLWQCFLES SQSVHPGVTV HPPPSTGLDG AKLHCCSKAN TSTCRELCTK LYSMSWGNTQ SWQ EFDRFC EYNPVEVSML TCLADVREPC QLGCRNLTYC TNFNNRPTEL FRSCNAQSDQ GAMNDMKLWE KGSIKMPFIN IPVL DIKKC QPEMWKAIAC SLQIKPCHSK SRGSIICKSD CVEILKKCGD QNKFPEDHTA ESICELLSPT DDLKNCIPLD TYLRP STLG NIVEEVTHPC NPNPCPANEL CEVNRKGCPS GDPCLPYFCV QGCKLGEASD FIVRQGTLIQ VPSSAGEVGC YKICSC GQS GLLENCMEMH CIDLQKSCIV GGKRKSHGTS FSIDCNVCSC FAGNLVCSTR LCLSEHSSED DRRTFTGLPC NCADQFV PV CGQNGRTYPS ACIARCVGLQ DHQFEFGSCM SKDPCNPNPC QKNQRCIPKP QVCLTTFDKF GCSQYECVPR QLACDQVQ D PVCDTDHMEH NNLCTLYQRG KSLSYKGPCQ PFCRATEPVC GHNGETYSSV CAAYSDRVAV DYYGDCQAVG VLSEHSSVA ECASVKCPSL LAAGCKPIIP PGACCPLCAG MLRVLFDKEK LDTIAKVTNK KPITVLEILQ KIRMHVSVPQ CDVFGYFSIE SEIVILIIP VDHYPKALQI EACNKEAEKI ESLINSDSPT LASHVPLSAL IISQVQVSSS VPSAGVRARP SCHSLLLPLS L GLALHLLW TYN

UniProtKB: Reversion-inducing cysteine-rich protein with Kazal motifs

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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: (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: 5 / 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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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: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 87543
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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