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- EMDB-36261: FZD6 Gs complex -

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Basic information

Entry
Database: EMDB / ID: EMD-36261
TitleFZD6 Gs complex
Map data
Sample
  • Complex: FZD6-Gs complex with Nb35.
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: Frizzled-6
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 / sensory perception of chemical stimulus / Wnt-protein binding / mu-type opioid receptor binding ...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 / sensory perception of chemical stimulus / Wnt-protein binding / mu-type opioid receptor binding / apicolateral plasma membrane / corticotropin-releasing hormone receptor 1 binding / PCP/CE pathway / Class B/2 (Secretin family receptors) / Wnt signaling pathway, planar cell polarity pathway / beta-2 adrenergic receptor binding / inner ear morphogenesis / PKA activation in glucagon signalling / D1 dopamine receptor binding / hair follicle development / developmental growth / canonical Wnt signaling pathway / Hedgehog 'off' state / Regulation of FZD by ubiquitination / ionotropic glutamate receptor binding / insulin-like growth factor receptor binding / adenylate cyclase activator activity / neural tube closure / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / negative regulation of canonical Wnt signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / cytoplasmic vesicle membrane / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / negative regulation of DNA-binding transcription factor activity / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / Glucagon-type ligand receptors / platelet activation / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / G alpha (12/13) signalling events / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / apical plasma membrane / lysosomal membrane / GTPase activity / synapse / ubiquitin protein ligase binding / protein-containing complex binding / GTP binding / endoplasmic reticulum membrane / cell surface / signal transduction / extracellular exosome / 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. / G-protein alpha subunit, group S / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Frizzled-6 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
Similarity search - Component
Biological speciesHomo sapiens (human)
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_36261.png

Downloads & links

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Map

FileDownload / File: emd_36261.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: 0.0283
Minimum - Maximum-0.001757698 - 1.9703306
Average (Standard dev.)0.001273811 (±0.025664462)
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: #1

Fileemd_36261_additional_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_36261_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #2

Fileemd_36261_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : FZD6-Gs complex with Nb35.

EntireName: FZD6-Gs complex with Nb35.
Components
  • Complex: FZD6-Gs complex with Nb35.
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: Frizzled-6

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Supramolecule #1: FZD6-Gs complex with Nb35.

SupramoleculeName: FZD6-Gs complex with Nb35. / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
type: protein_or_peptide / ID: 1 / Details: minGas / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.117201 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: HHHHHHENLY FQGSKTEDKR AQKRAEKKRS KLIDKQLQDE KMGYMCTHRL LLLGADNSGK STIVKQMRIL HGGSGGSGGT SGIFETKFQ VDKVNFHMFD VGGQRDERRK WIQCFNDVTA IIFVVDSSDY GSGGSGAGSA NRLQEALNLF KSIWNNRWLR T ISVILFLN ...String:
HHHHHHENLY FQGSKTEDKR AQKRAEKKRS KLIDKQLQDE KMGYMCTHRL LLLGADNSGK STIVKQMRIL HGGSGGSGGT SGIFETKFQ VDKVNFHMFD VGGQRDERRK WIQCFNDVTA IIFVVDSSDY GSGGSGAGSA NRLQEALNLF KSIWNNRWLR T ISVILFLN KQDLLAEKVL AGKSKIEDYF PEFARYTTPE DATPEPGEDP RVTRAKYFIR DEFLRISTAS GDGRHYCYPH FT CAVDTEN ARRIFNDCRD IIQRMHLRQY ELL

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas, Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas, Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 8.417766 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MHHHHHHNTA SIAQARKLVE QLKMEANIDR IKVSKAAADL MAYCEAHAKE DPLLTPVPAS ENPFREKKFF CAIL

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 14.845516 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MQVQLQESGG GLVQPGGSLR LSCAASGFTF SNYKMNWVRQ APGKGLEWVS DISQSGASIS YTGSVKGRFT ISRDNAKNTL YLQMNSLKP EDTAVYYCAR CPAPFTRDCF DVTSTTYAYR GQGTQVTVSS HHHHHH

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Macromolecule #5: Frizzled-6

MacromoleculeName: Frizzled-6 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 61.912398 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKHHHHHH HSLFTCEPIT VPRCMKMAYN MTFFPNLMGH YDQSIAAVEM EHFLPLANLE CSPNIETFL CKAFVPTCIE QIHVVPPCRK LCEKVYSDCK KLIDTFGIRW PEELECDRLQ YCDETVPVTF DPHTEFLGPQ K KTEQVQRD ...String:
MKTIIALSYI FCLVFADYKD DDDKHHHHHH HSLFTCEPIT VPRCMKMAYN MTFFPNLMGH YDQSIAAVEM EHFLPLANLE CSPNIETFL CKAFVPTCIE QIHVVPPCRK LCEKVYSDCK KLIDTFGIRW PEELECDRLQ YCDETVPVTF DPHTEFLGPQ K KTEQVQRD IGFWCPRHLK TSGGQGYKFL GIDQCAPPCP NMYFKSDELE FAKSFIGTVS IFCLCATLFT FLTFLIDVRR FR YPERPII YYSVCYSIVS LMYFIGFLLG DSTACNKADE KLELGDTVVL GSQNKACTVL FMLLYFFTMA GTVWWVILTI TWF LAAGRK WSCEAIEQKA VWFHAVAWGT PGFLTVMLLA MNKVEGDNIS GVCFVGLYDL DASRYFVLLP LCLCVFVGLS LLLA GIISL NHVRQVIQHD GRNQEKLKKF MIRIGVFSGL YLVPLVTLLG CYVYEQVNRI TWEITWVSDH CRQYHIPCPY QAKAK ARPE LALFMIKYLM TLIVGISAVF WVGSKKTCTE WAGFFKRNRK RDPISESRRV LQE

UniProtKB: 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: DIFFRACTION / Nominal defocus max: 2.0 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: 530390
FSC plot (resolution estimation)

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