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- PDB-8j9o: Cryo-EM structure of inactive FZD1 -

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Basic information

Entry
Database: PDB / ID: 8j9o
TitleCryo-EM structure of inactive FZD1
Components
  • Frizzled-1,Soluble cytochrome b562
  • anti-BRIL Fab Heavy Chain
  • anti-BRIL Fab Light Chain
  • anti-Fab nanobody
KeywordsMEMBRANE PROTEIN / Frizzled / class-F / FZD1 / Complex
Function / homology
Function and homology information


: / muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / planar cell polarity pathway involved in neural tube closure / astrocyte-dopaminergic neuron signaling / canonical Wnt signaling pathway involved in mesenchymal stem cell differentiation / hard palate development / Wnt receptor activity / membranous septum morphogenesis ...: / muscular septum morphogenesis / regulation of mesenchymal stem cell differentiation / autocrine signaling / planar cell polarity pathway involved in neural tube closure / astrocyte-dopaminergic neuron signaling / canonical Wnt signaling pathway involved in mesenchymal stem cell differentiation / hard palate development / Wnt receptor activity / membranous septum morphogenesis / non-canonical Wnt signaling pathway / presynapse assembly / endothelial cell differentiation / Wnt-protein binding / midbrain dopaminergic neuron differentiation / negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway / frizzled binding / PCP/CE pathway / Wnt signalosome / Class B/2 (Secretin family receptors) / Disassembly of the destruction complex and recruitment of AXIN to the membrane / outflow tract morphogenesis / regulation of presynapse assembly / negative regulation of BMP signaling pathway / canonical Wnt signaling pathway / positive regulation of osteoblast differentiation / Asymmetric localization of PCP proteins / TCF dependent signaling in response to WNT / electron transport chain / G protein-coupled receptor activity / PDZ domain binding / neuron differentiation / negative regulation of canonical Wnt signaling pathway / positive regulation of DNA-binding transcription factor activity / positive regulation of neuron projection development / cell-cell signaling / periplasmic space / electron transfer activity / response to xenobiotic stimulus / iron ion binding / positive regulation of protein phosphorylation / signaling receptor binding / focal adhesion / negative regulation of DNA-templated transcription / heme binding / positive regulation of DNA-templated transcription / cell surface / plasma membrane
Similarity search - Function
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. / GPCR, family 2-like ...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. / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562
Similarity search - Domain/homology
Soluble cytochrome b562 / Frizzled-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Escherichia coli (E. coli)
Mus (mice)
Vicugna pacos (alpaca)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsLin, X. / Xu, F.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Cell Discov / Year: 2024
Title: A framework for Frizzled-G protein coupling and implications to the PCP signaling pathways.
Authors: Zhibin Zhang / Xi Lin / Ling Wei / Yiran Wu / Lu Xu / Lijie Wu / Xiaohu Wei / Suwen Zhao / Xiangjia Zhu / Fei Xu /
Abstract: The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. ...The ten Frizzled receptors (FZDs) are essential in Wnt signaling and play important roles in embryonic development and tumorigenesis. Among these, FZD6 is closely associated with lens development. Understanding FZD activation mechanism is key to unlock these emerging targets. Here we present the cryo-EM structures of FZD6 and FZD3 which are known to relay non-canonical planar cell polarity (PCP) signaling pathways as well as FZD1 in their G protein-coupled states and in the apo inactive states, respectively. Comparison of the three inactive/active pairs unveiled a shared activation framework among all ten FZDs. Mutagenesis along with imaging and functional analysis on the human lens epithelial tissues suggested potential crosstalk between the G-protein coupling of FZD6 and the PCP signaling pathways. Together, this study provides an integrated understanding of FZD structure and function, and lays the foundation for developing therapeutic modulators to activate or inhibit FZD signaling for a range of disorders including cancers and cataracts.
History
DepositionMay 4, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 17, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Frizzled-1,Soluble cytochrome b562
B: anti-BRIL Fab Heavy Chain
C: anti-Fab nanobody
D: anti-BRIL Fab Light Chain


Theoretical massNumber of molelcules
Total (without water)141,0184
Polymers141,0184
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Frizzled-1,Soluble cytochrome b562 / Fz-1 / hFz1 / FzE1


Mass: 75034.164 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: inactive FZD1
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: FZD1, cybC / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UP38, UniProt: P0ABE7
#2: Antibody anti-BRIL Fab Heavy Chain


Mass: 28035.420 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus (mice) / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper)
#3: Antibody anti-Fab nanobody


Mass: 13390.644 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Vicugna pacos (alpaca) / Production host: Escherichia coli (E. coli)
#4: Antibody anti-BRIL Fab Light Chain


Mass: 24557.408 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus (mice) / Cell line (production host): Hi5 / Production host: Trichoplusia ni (cabbage looper)

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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: Frizzled-1 with ICL3-BRIL complex with anti-BRIL Fab / Type: COMPLEX / Entity ID: all / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Escherichia coli (E. coli)562
31Mus (mice)10088
41Vicugna pacos (alpaca)30538
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Trichoplusia ni (cabbage looper)7111
31Escherichia coli (E. coli)562
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: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2200 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 327768 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0057826
ELECTRON MICROSCOPYf_angle_d0.69910644
ELECTRON MICROSCOPYf_dihedral_angle_d4.0151081
ELECTRON MICROSCOPYf_chiral_restr0.041195
ELECTRON MICROSCOPYf_plane_restr0.0071344

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