+Open data
-Basic information
Entry | Database: PDB / ID: 8wm9 | ||||||
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Title | Fzd4/DEP complex | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR complex | ||||||
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 / convergent extension involved in neural plate elongation / retinal blood vessel morphogenesis / 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 / convergent extension involved in neural plate elongation / retinal blood vessel morphogenesis / 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 / WNT5:FZD7-mediated leishmania damping / establishment of blood-brain barrier / frizzled binding / PCP/CE pathway / Signaling by Hippo / Class B/2 (Secretin family receptors) / WNT mediated activation of DVL / positive regulation of dendrite morphogenesis / negative regulation of cell-substrate adhesion / Disassembly of the destruction complex and recruitment of AXIN to the membrane / cytokine receptor activity / aggresome / Wnt signaling pathway, planar cell polarity pathway / heart looping / cytokine binding / outflow tract morphogenesis / lateral plasma membrane / vasculogenesis / canonical Wnt signaling pathway / 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 / TCF dependent signaling in response to WNT / Asymmetric localization of PCP proteins / regulation of actin cytoskeleton organization / RHO GTPases Activate Formins / PDZ domain binding / G protein-coupled receptor activity / Degradation of DVL / positive regulation of JNK cascade / positive regulation of DNA-binding transcription factor activity / sensory perception of sound / clathrin-coated endocytic vesicle membrane / neuron differentiation / Wnt signaling pathway / small GTPase binding / cell-cell junction / protein localization / Cargo recognition for clathrin-mediated endocytosis / apical part of cell / heart development / Clathrin-mediated endocytosis / signaling receptor activity / amyloid-beta binding / Ca2+ pathway / regulation of cell population proliferation / protein-macromolecule adaptor activity / cytoplasmic vesicle / angiogenesis / cell population proliferation / nuclear body / response to hypoxia / intracellular signal transduction / positive regulation of cell migration / protein heterodimerization activity / positive regulation of protein phosphorylation / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.53 Å | ||||||
Authors | He, Y. / Qian, Y. | ||||||
Funding support | China, 1items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8wm9.cif.gz | 160 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8wm9.ent.gz | 116.3 KB | Display | PDB format |
PDBx/mmJSON format | 8wm9.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8wm9_validation.pdf.gz | 1.5 MB | Display | wwPDB validaton report |
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Full document | 8wm9_full_validation.pdf.gz | 1.6 MB | Display | |
Data in XML | 8wm9_validation.xml.gz | 39.8 KB | Display | |
Data in CIF | 8wm9_validation.cif.gz | 55.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/wm/8wm9 ftp://data.pdbj.org/pub/pdb/validation_reports/wm/8wm9 | HTTPS FTP |
-Related structure data
Related structure data | 37646MC 8wmaC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 | | 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 / Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: GPCR complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT |
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Molecular weight | Value: 0.45 MDa / Experimental value: NO |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 95333 / Symmetry type: POINT |