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- EMDB-36258: FZD6 in inactive state -

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Basic information

Entry
Database: EMDB / ID: EMD-36258
TitleFZD6 in inactive state
Map data
Sample
  • Complex: Complex of human FZD6 in inactivate state with accessory proteins.
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-Fab Nanobody
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: Frizzled-6,Soluble cytochrome b562
KeywordsFZD6 / Complex. / MEMBRANE PROTEIN
Function / homology
Function and homology information


embryonic nail plate morphogenesis / establishment of body hair planar orientation / cell proliferation in midbrain / Signaling by RNF43 mutants / Wnt receptor activity / midbrain morphogenesis / non-canonical Wnt signaling pathway / Wnt-protein binding / apicolateral plasma membrane / PCP/CE pathway ...embryonic nail plate morphogenesis / establishment of body hair planar orientation / cell proliferation in midbrain / Signaling by RNF43 mutants / Wnt receptor activity / midbrain morphogenesis / non-canonical Wnt signaling pathway / Wnt-protein binding / apicolateral plasma membrane / PCP/CE pathway / Class B/2 (Secretin family receptors) / Wnt signaling pathway, planar cell polarity pathway / inner ear morphogenesis / hair follicle development / canonical Wnt signaling pathway / Regulation of FZD by ubiquitination / neural tube closure / G protein-coupled receptor activity / negative regulation of canonical Wnt signaling pathway / cytoplasmic vesicle membrane / negative regulation of DNA-binding transcription factor activity / platelet activation / Ca2+ pathway / electron transfer activity / periplasmic space / iron ion binding / apical plasma membrane / ubiquitin protein ligase binding / heme binding / endoplasmic reticulum membrane / cell surface / plasma membrane
Similarity search - Function
Frizzled-6 / Frizzled 6, 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-6 / Frizzled 6, 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
Frizzled-6 / Soluble cytochrome b562
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsXu F / Zhang Z
Funding support China, 1 items
OrganizationGrant numberCountry
Not funded China
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 22, 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_36258.png

Downloads & links

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Map

FileDownload / File: emd_36258.map.gz / Format: CCP4 / Size: 125 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-0.0017968935 - 2.2186007
Average (Standard dev.)0.0009197531 (±0.02219321)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_36258_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36258_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36258_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of human FZD6 in inactivate state with accessory proteins.

EntireName: Complex of human FZD6 in inactivate state with accessory proteins.
Components
  • Complex: Complex of human FZD6 in inactivate state with accessory proteins.
    • Protein or peptide: anti-BRIL Fab Heavy chain
    • Protein or peptide: anti-Fab Nanobody
    • Protein or peptide: anti-BRIL Fab Light chain
    • Protein or peptide: Frizzled-6,Soluble cytochrome b562

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Supramolecule #1: Complex of human FZD6 in inactivate state with accessory proteins.

SupramoleculeName: Complex of human FZD6 in inactivate state with accessory proteins.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: anti-BRIL Fab Heavy chain

MacromoleculeName: anti-BRIL Fab Heavy chain / type: protein_or_peptide / ID: 1 / 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 #2: anti-Fab Nanobody

MacromoleculeName: anti-Fab Nanobody / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 14.075395 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
HHHHHHQVQL QESGGGLVQP GGSLRLSCAA SGRTISRYAM SWFRQAPGKE REFVAVARRS GDGAFYADSV QGRFTVSRDD AKNTVYLQM NSLKPEDTAV YYCAIDSDTF YSGSYDYWGQ GTQVTVSS

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Macromolecule #3: anti-BRIL Fab Light chain

MacromoleculeName: anti-BRIL Fab Light chain / type: protein_or_peptide / ID: 3 / 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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Macromolecule #4: Frizzled-6,Soluble cytochrome b562

MacromoleculeName: Frizzled-6,Soluble cytochrome b562 / type: protein_or_peptide / ID: 4 / Details: inactive FZD6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.464352 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GHSLFTCEPI TVPRCMKMAY NMTFFPNLMG HYDQSIAAVE MEHFLPLAN LECSPNIETF LCKAFVPTCI EQIHVVPPCR KLCEKVYSDC KKLIDTFGIR WPEELECDRL QYCDETVPVT F DPHTEFLG ...String:
MKTIIALSYI FCLVFADYKD DDDKHHHHHH HHHHENLYFQ GHSLFTCEPI TVPRCMKMAY NMTFFPNLMG HYDQSIAAVE MEHFLPLAN LECSPNIETF LCKAFVPTCI EQIHVVPPCR KLCEKVYSDC KKLIDTFGIR WPEELECDRL QYCDETVPVT F DPHTEFLG PQKKTEQVQR DIGFWCPRHL KTSGGQGYKF LGIDQCAPPC PNMYFKSDEL EFAKSFIGTV SIFCLCATLF TF LTFLIDV RRFRYPERPI IYYSVCYSIV SLMYFIGFLL GDSTACNKAD EKLELGDTVV LGSQNKACTV LFMLLYFFTM AGT VWWVIL TITWFLAAGR KWSCEAIEQK AVWFHAVAWG TPGFLTVMLL AMNKVEGDNI SGVCFVGLYD LDASRYFVLL PLCL CVFVG LSLLLAGIIS LNHVARRQLA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KATPPKLEDK SPDSP EMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLERAR STLEEKLKKF MIRIGVFSGL YLVPLV TLL GCYVYEQVNR ITWEITWVSD HCRQYHIPCP YQAKAKARPE LALFMIKYLM TLIVGISAVF WVGSKKTCTE WAGFFKR N

UniProtKB: Frizzled-6, Soluble cytochrome b562, Frizzled-6

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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: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 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: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 660274
FSC plot (resolution estimation)

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