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- EMDB-37646: Fzd4/DEP complex -

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Basic information

Entry
Database: EMDB / ID: EMD-37646
TitleFzd4/DEP complex
Map data
Sample
  • Complex: GPCR complex
    • Protein or peptide: Frizzled-4
    • Protein or peptide: Segment polarity protein dishevelled homolog DVL-2
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsGPCR complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


cerebellum vasculature morphogenesis / Wnt signaling pathway, calcium modulating pathway / Norrin signaling pathway / extracellular matrix-cell signaling / Negative regulation of TCF-dependent signaling by DVL-interacting proteins / progesterone secretion / retinal blood vessel morphogenesis / convergent extension involved in neural plate elongation / locomotion involved in locomotory behavior / retina vasculature morphogenesis in camera-type eye ...cerebellum vasculature morphogenesis / Wnt signaling pathway, calcium modulating pathway / Norrin signaling pathway / extracellular matrix-cell signaling / Negative regulation of TCF-dependent signaling by DVL-interacting proteins / progesterone secretion / retinal blood vessel morphogenesis / convergent extension involved in neural plate elongation / locomotion involved in locomotory behavior / retina vasculature morphogenesis in camera-type eye / regulation of vascular endothelial growth factor receptor signaling pathway / : / cochlea morphogenesis / Signaling by RNF43 mutants / segment specification / WNT5A-dependent internalization of FZD4 / Wnt receptor activity / positive regulation of neuron projection arborization / non-canonical Wnt signaling pathway / Wnt-protein binding / endothelial cell differentiation / clathrin-coated endocytic vesicle / establishment of blood-brain barrier / WNT5:FZD7-mediated leishmania damping / frizzled binding / PCP/CE pathway / Class B/2 (Secretin family receptors) / Signaling by Hippo / WNT mediated activation of DVL / cytokine receptor activity / positive regulation of dendrite morphogenesis / negative regulation of cell-substrate adhesion / Disassembly of the destruction complex and recruitment of AXIN to the membrane / aggresome / Wnt signaling pathway, planar cell polarity pathway / heart looping / cytokine binding / outflow tract morphogenesis / lateral plasma membrane / canonical Wnt signaling pathway / vasculogenesis / cellular response to retinoic acid / positive regulation of JUN kinase activity / Regulation of FZD by ubiquitination / substrate adhesion-dependent cell spreading / cellular response to leukemia inhibitory factor / neural tube closure / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / regulation of actin cytoskeleton organization / Degradation of DVL / RHO GTPases Activate Formins / G protein-coupled receptor activity / PDZ domain binding / sensory perception of sound / positive regulation of JNK cascade / positive regulation of DNA-binding transcription factor activity / clathrin-coated endocytic vesicle membrane / neuron differentiation / small GTPase binding / Wnt signaling pathway / cell-cell junction / protein localization / Cargo recognition for clathrin-mediated endocytosis / apical part of cell / Clathrin-mediated endocytosis / signaling receptor activity / heart development / regulation of cell population proliferation / Ca2+ pathway / protein-macromolecule adaptor activity / amyloid-beta binding / cytoplasmic vesicle / angiogenesis / cell population proliferation / response to hypoxia / nuclear body / intracellular signal transduction / positive regulation of cell migration / positive regulation of protein phosphorylation / protein heterodimerization activity / protein domain specific binding / glutamatergic synapse / ubiquitin protein ligase binding / dendrite / protein-containing complex binding / regulation of DNA-templated transcription / protein kinase binding / positive regulation of DNA-templated transcription / cell surface / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Frizzled-4 / Frizzled 4, cysteine-rich domain / Dishevelled-2 / Dishevelled protein domain / Dishevelled family / Dishevelled C-terminal / Dishevelled specific domain / Segment polarity protein dishevelled (Dsh) C terminal / Dishevelled-related protein / DIX domain ...Frizzled-4 / Frizzled 4, cysteine-rich domain / Dishevelled-2 / Dishevelled protein domain / Dishevelled family / Dishevelled C-terminal / Dishevelled specific domain / Segment polarity protein dishevelled (Dsh) C terminal / Dishevelled-related protein / DIX domain / DIX domain superfamily / DIX domain / DIX domain profile. / Domain present in Dishevelled and axin / Frizzled/Smoothened, transmembrane domain / Frizzled/Smoothened family membrane region / Frizzled/Smoothened family membrane region / Frizzled/secreted frizzled-related protein / Frizzled / Frizzled domain / Frizzled cysteine-rich domain superfamily / Fz domain / Frizzled (fz) domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / PDZ domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Ubiquitin-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Segment polarity protein dishevelled homolog DVL-2 / Frizzled-4
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsHe Y / Qian Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32070048 China
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation.
Authors: Yu Qian / Zhengxiong Ma / Zhenmei Xu / Yaning Duan / Yangjie Xiong / Ruixue Xia / Xinyan Zhu / Zongwei Zhang / Xinyu Tian / Han Yin / Jian Liu / Jing Song / Yang Lu / Anqi Zhang / Changyou ...Authors: Yu Qian / Zhengxiong Ma / Zhenmei Xu / Yaning Duan / Yangjie Xiong / Ruixue Xia / Xinyan Zhu / Zongwei Zhang / Xinyu Tian / Han Yin / Jian Liu / Jing Song / Yang Lu / Anqi Zhang / Changyou Guo / Lihua Jin / Woo Jae Kim / Jiyuan Ke / Fei Xu / Zhiwei Huang / Yuanzheng He /
Abstract: WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with ...WNT signaling is fundamental in development and homeostasis, but how the Frizzled receptors (FZDs) propagate signaling remains enigmatic. Here, we present the cryo-EM structure of FZD4 engaged with the DEP domain of Dishevelled 2 (DVL2), a key WNT transducer. We uncover a distinct binding mode where the DEP finger-loop inserts into the FZD4 cavity to form a hydrophobic interface. FZD4 intracellular loop 2 (ICL2) additionally anchors the complex through polar contacts. Mutagenesis validates the structural observations. The DEP interface is highly conserved in FZDs, indicating a universal mechanism by which FZDs engage with DVLs. We further reveal that DEP mimics G-protein/β-arrestin/GRK to recognize an active conformation of receptor, expanding current GPCR engagement models. Finally, we identify a distinct FZD4 dimerization interface. Our findings delineate the molecular determinants governing FZD/DVL assembly and propagation of WNT signaling, providing long-sought answers underlying WNT signal transduction.
History
DepositionOct 3, 2023-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateSep 11, 2024-
Current statusSep 11, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37646.png

Downloads & links

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Map

FileDownload / File: emd_37646.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å		1.1 Å/pix.
x 256 pix.
= 281.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.015808983 - 2.1303434
Average (Standard dev.)0.0008395209 (±0.018268261)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_37646_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #2

Fileemd_37646_half_map_2.map
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Sample components

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Entire : GPCR complex

EntireName: GPCR complex
Components
  • Complex: GPCR complex
    • Protein or peptide: Frizzled-4
    • Protein or peptide: Segment polarity protein dishevelled homolog DVL-2
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: GPCR complex

SupramoleculeName: GPCR complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 450 KDa

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Macromolecule #1: Frizzled-4

MacromoleculeName: Frizzled-4 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.047922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAWRGAGPSV PGAPGGVGLS LGLLLQLLLL LGPARGFGDE EERRCDPIRI SMCQNLGYNV TKMPNLVGHE LQTDAELQLT TFTPLIQYG CSSQLQFFLC SVYVPMCTEK INIPIGPCGG MCLSVKRRCE PVLKEFGFAW PESLNCSKFP PQNDHNHMCM E GPGDEEVP ...String:
MAWRGAGPSV PGAPGGVGLS LGLLLQLLLL LGPARGFGDE EERRCDPIRI SMCQNLGYNV TKMPNLVGHE LQTDAELQLT TFTPLIQYG CSSQLQFFLC SVYVPMCTEK INIPIGPCGG MCLSVKRRCE PVLKEFGFAW PESLNCSKFP PQNDHNHMCM E GPGDEEVP LPHKTPIQPG EECHSVGTNS DQYIWVKRSL NCVLKCGYDA GLYSRSAKEF TDIWMAVWAS LCFISTAFTV LT FLIDSSR FSYPERPIIF LSMCYNIYSI AYIVRLTVGR ERISCDFEEA AEPVLIQEGL KNTGCAIIFL LLYFFGMASS IWW VILTLT WFLAAGLKWG HEAIEMHSSY FHIAAWAIPA VKTIVILIMR LVDADELTGL CYVGNQNLDA LTGFVVAPLF TYLV IGTLF IAAGLVALFK IRSNLQKDGT KTDKLERLMV KIGVFSVLYT VPATIVIACY FYEISNWALF RYSADDSNMA VEMLK IFMS LLVGITSGMW IWSAKTLHTW QKFYNRLVNS GKVKREKRGN GWVKPGKGSE TVV

UniProtKB: Frizzled-4

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Macromolecule #2: Segment polarity protein dishevelled homolog DVL-2

MacromoleculeName: Segment polarity protein dishevelled homolog DVL-2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 79.035953 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAGSSTGGGG VGETKVIYHL DEEETPYLVK IPVPAERITL GDFKSVLQRP AGAKYFFKSM DQDFGVVKEE ISDDNARLPC FNGRVVSWL VSSDNPQPEM APPVHEPRAE LAPPAPPLPP LPPERTSGIG DSRPPSFHPN VSSSHENLEP ETETESVVSL R RERPRRRD ...String:
MAGSSTGGGG VGETKVIYHL DEEETPYLVK IPVPAERITL GDFKSVLQRP AGAKYFFKSM DQDFGVVKEE ISDDNARLPC FNGRVVSWL VSSDNPQPEM APPVHEPRAE LAPPAPPLPP LPPERTSGIG DSRPPSFHPN VSSSHENLEP ETETESVVSL R RERPRRRD SSEHGAGGHR TGGPSRLERH LAGYESSSTL MTSELESTSL GDSDEEDTMS RFSSSTEQSS ASRLLKRHRR RR KQRPPRL ERTSSFSSVT DSTMSLNIIT VTLNMEKYNF LGISIVGQSN ERGDGGIYIG SIMKGGAVAA DGRIEPGDML LQV NDMNFE NMSNDDAVRV LRDIVHKPGP IVLTVAKCWD PSPQAYFTLP RNEPIQPIDP AAWVSHSAAL TGTFPAYPGS SSMS TITSG SSLPDGCEGR GLSVHTDMAS VTKAMAAPES GLEVRDRMWL KITIPNAFLG SDVVDWLYHH VEGFPERREA RKYAS GLLK AGLIRHTVNK ITFSEQCYYV FGDLSGGCES YLVNLSLNDN DGSSGASDQD TLAPLPGATP WPLLPTFSYQ YPAPHP YSP QPPPYHELSS YTYGGGSASS QHSEGSRSSG STRSDGGAGR TGRPEERAPE SKSGSGSESE PSSRGGSLRR GGEASGT SD GGPPPSRGST GGAPNLRAHP GLHPYGPPPG MALPYNPMMV VMMPPPPPPV PPAVQPPGAP PVRDLGSVPP ELTASRQS F HMAMGNPSEF FVDVM

UniProtKB: Segment polarity protein dishevelled homolog DVL-2

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 10 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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 K2 SUMMIT (4k 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: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 95333
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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