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- PDB-8wm9: Fzd4/DEP complex -

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Basic information

Entry
Database: PDB / ID: 8wm9
TitleFzd4/DEP complex
Components
  • Frizzled-4
  • Segment polarity protein dishevelled homolog DVL-2
KeywordsMEMBRANE PROTEIN / GPCR complex
Function / homology
Function and homology information


cerebellum vasculature morphogenesis / Wnt signaling pathway, calcium modulating pathway / Norrin signaling pathway / Negative regulation of TCF-dependent signaling by DVL-interacting proteins / extracellular matrix-cell signaling / progesterone secretion / retinal blood vessel morphogenesis / convergent extension involved in neural plate elongation / retina vasculature morphogenesis in camera-type eye / locomotion involved in locomotory behavior ...cerebellum vasculature morphogenesis / Wnt signaling pathway, calcium modulating pathway / Norrin signaling pathway / Negative regulation of TCF-dependent signaling by DVL-interacting proteins / extracellular matrix-cell signaling / progesterone secretion / retinal blood vessel morphogenesis / convergent extension involved in neural plate elongation / retina vasculature morphogenesis in camera-type eye / locomotion involved in locomotory behavior / Signaling by RNF43 mutants / segment specification / WNT5A-dependent internalization of FZD4 / regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of neuron projection arborization / Wnt receptor activity / non-canonical Wnt signaling pathway / endothelial cell differentiation / cochlea morphogenesis / Wnt-protein binding / clathrin-coated endocytic vesicle / WNT5:FZD7-mediated leishmania damping / positive regulation of dendrite morphogenesis / establishment of blood-brain barrier / frizzled binding / Signaling by Hippo / PCP/CE pathway / cytokine receptor activity / Class B/2 (Secretin family receptors) / WNT mediated activation of DVL / Disassembly of the destruction complex and recruitment of AXIN to the membrane / Wnt signaling pathway, planar cell polarity pathway / aggresome / heart looping / cytokine binding / outflow tract morphogenesis / lateral plasma membrane / positive regulation of signal transduction by p53 class mediator / negative regulation of cell-substrate adhesion / canonical Wnt signaling pathway / vasculogenesis / cellular response to retinoic acid / Regulation of FZD by ubiquitination / substrate adhesion-dependent cell spreading / cellular response to leukemia inhibitory factor / TCF dependent signaling in response to WNT / Asymmetric localization of PCP proteins / regulation of actin cytoskeleton organization / neural tube closure / positive regulation of JNK cascade / PDZ domain binding / Degradation of DVL / clathrin-coated endocytic vesicle membrane / RHO GTPases Activate Formins / sensory perception of sound / G protein-coupled receptor activity / small GTPase binding / Wnt signaling pathway / neuron differentiation / apical part of cell / cell-cell junction / intracellular protein localization / Cargo recognition for clathrin-mediated endocytosis / signaling receptor activity / regulation of cell population proliferation / Clathrin-mediated endocytosis / amyloid-beta binding / heart development / Ca2+ pathway / cytoplasmic vesicle / angiogenesis / protein-macromolecule adaptor activity / response to hypoxia / cell population proliferation / intracellular signal transduction / nuclear body / cilium / positive regulation of cell migration / protein heterodimerization activity / protein domain specific binding / dendrite / ubiquitin protein ligase binding / regulation of DNA-templated transcription / protein kinase binding / positive regulation of DNA-templated transcription / protein-containing complex binding / glutamatergic synapse / cell surface / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
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
CHOLESTEROL HEMISUCCINATE / Segment polarity protein dishevelled homolog DVL-2 / Frizzled-4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsHe, Y. / Qian, Y.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 11, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Frizzled-4
B: Frizzled-4
C: Segment polarity protein dishevelled homolog DVL-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)203,99913
Polymers199,1323
Non-polymers4,86710
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Frizzled-4


Mass: 60047.922 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FZD4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9ULV1
#2: Protein Segment polarity protein dishevelled homolog DVL-2 / DEP


Mass: 79035.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DVL2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O14641
#3: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C31H50O4
Has ligand of interestN
Has protein modificationY

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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

ComponentName: GPCR complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.45 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
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 FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95333 / Symmetry type: POINT

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