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- EMDB-36262: FZD3 in inactive state -

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Basic information

Entry
Database: EMDB / ID: EMD-36262
TitleFZD3 in inactive state
Map data
Sample
  • Complex: complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody
    • Protein or peptide: Frizzled-3,Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-Fab Nanobody
    • Protein or peptide: anti-BRIL Fab Light chain
KeywordsFZD3 / complex. / MEMBRANE PROTEIN
Function / homology
Function and homology information


dopaminergic neuron axon guidance / serotonergic neuron axon guidance / cell proliferation in midbrain / establishment of planar polarity / negative regulation of mitotic cell cycle, embryonic / Wnt receptor activity / midbrain morphogenesis / non-canonical Wnt signaling pathway / motor neuron migration / sympathetic ganglion development ...dopaminergic neuron axon guidance / serotonergic neuron axon guidance / cell proliferation in midbrain / establishment of planar polarity / negative regulation of mitotic cell cycle, embryonic / Wnt receptor activity / midbrain morphogenesis / non-canonical Wnt signaling pathway / motor neuron migration / sympathetic ganglion development / filopodium tip / Wnt-protein binding / post-anal tail morphogenesis / negative regulation of execution phase of apoptosis / commissural neuron axon guidance / PCP/CE pathway / Class B/2 (Secretin family receptors) / Wnt signaling pathway, planar cell polarity pathway / inner ear morphogenesis / positive regulation of neuroblast proliferation / presynaptic active zone / hair follicle development / canonical Wnt signaling pathway / lateral plasma membrane / response to electrical stimulus / Asymmetric localization of PCP proteins / neural tube closure / PDZ domain binding / G protein-coupled receptor activity / neuron differentiation / Ca2+ pathway / electron transfer activity / periplasmic space / response to xenobiotic stimulus / iron ion binding / apical plasma membrane / axon / neuronal cell body / dendrite / heme binding / cell surface / plasma membrane / cytoplasm
Similarity search - Function
Frizzled 3, cysteine-rich domain / 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. ...Frizzled 3, cysteine-rich domain / 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-3
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsXu F / Zhang Z
Funding support1 items
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 23, 2023-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36262.png

Downloads & links

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Map

FileDownload / File: emd_36262.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.043
Minimum - Maximum-0.001774758 - 2.0198398
Average (Standard dev.)0.001217879 (±0.02499804)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 239.616 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: mask used in the last local refine.

Fileemd_36262_additional_1.map
Annotationmask used in the last local refine.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: default sharpened density map after the last local refine

Fileemd_36262_additional_2.map
Annotationdefault sharpened density map after the last local refine
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36262_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36262_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 : complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody

EntireName: complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody
Components
  • Complex: complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody
    • Protein or peptide: Frizzled-3,Soluble cytochrome b562
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-Fab Nanobody
    • Protein or peptide: anti-BRIL Fab Light chain

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Supramolecule #1: complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody

SupramoleculeName: complex of FZD3 with anti-Bril Fab and anti-Fab Nanobody
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Frizzled-3,Soluble cytochrome b562

MacromoleculeName: Frizzled-3,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Details: inactive FZD3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.095141 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GHSLFSCEPI TLRMCQDLPY NTTFMPNLLN HYDQQTAALA MEPFHPMVN LDCSRDFRPF LCALYAPICM EYGRVTLPCR RLCQRAYSEC SKLMEMFGVP WPEDMECSRF PDCDEPYPRL V DLNLAGEP ...String:
MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GHSLFSCEPI TLRMCQDLPY NTTFMPNLLN HYDQQTAALA MEPFHPMVN LDCSRDFRPF LCALYAPICM EYGRVTLPCR RLCQRAYSEC SKLMEMFGVP WPEDMECSRF PDCDEPYPRL V DLNLAGEP TEGAPVAVQR DYGFWCPREL KIDPDLGYSF LHVRDCSPPC PNMYFRREEL SFARYFIGLI SIICLSATLF TF LTFLIDV TRFRYPERPI IFYAVCYMMV SLIFFIGFLL EDRVACNASI PAQYKASTVT QGSHNKACTM LFMILYFFTM AGS VWWVIL TITWFLAAVP KWGSEAIEKK ALLFHASAWG IPGTLTIILL AMNKIEGDNI SGVCFVGLYD VDALRYFVLA PLCL YVVVG VSLLLAGIIS LNRRIARRQL ADLEDNWETL NDNLKVIEKA DNAAQVKDAL TKMRAAALDA QKATPPKLED KSPDS PEMK DFRHGFDILV GQIDDALKLA NEGKVKEAQA AAEQLKTTRN AYIQKYLERA RSTLNQDKLV KFMIRIGVFS ILYLVP LLV VIGCYFYEQA YRGIWETTWI QERCREYHIP CPYQVTQMSR PDLILFLMKY LMALIVGIPS VFWVGSKKTC FEWASFF HG R

UniProtKB: Frizzled-3, Soluble cytochrome b562, Frizzled-3

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Macromolecule #2: anti-BRIL Fab Heavy chain

MacromoleculeName: anti-BRIL Fab Heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.704648 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFNVV DFSLHWVRQA PGKGLEWVAY ISSSSGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARW GYWPGEPWWK AFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFNVV DFSLHWVRQA PGKGLEWVAY ISSSSGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARW GYWPGEPWWK AFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKSLE VLFQGPHHHH HH

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Macromolecule #3: anti-Fab Nanobody

MacromoleculeName: anti-Fab Nanobody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 14.927301 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
HHHHHHENLY FQGQVQLQES GGGLVQPGGS LRLSCAASGR TISRYAMSWF RQAPGKEREF VAVARRSGDG AFYADSVQGR FTVSRDDAK NTVYLQMNSL KPEDTAVYYC AIDSDTFYSG SYDYWGQGTQ VTVSS

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Macromolecule #4: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.20982 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
DIQMTQSPSS LSASVGDRVT ITCRASQSVS SAVAWYQQKP GKAPKLLIYS ASSLYSGVPS RFSGSRSGTD FTLTISSLQP EDFATYYCQ QYLYYSLVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNR

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: DIFFRACTION / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 20.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 221700
FSC plot (resolution estimation)

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