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Protein

Frizzled-6

Gene

FZD6

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear (By similarity).By similarity

GO - Molecular functioni

  • G-protein coupled receptor activity Source: GO_Central
  • ubiquitin protein ligase binding Source: UniProtKB
  • Wnt-activated receptor activity Source: BHF-UCL
  • Wnt-protein binding Source: BHF-UCL

GO - Biological processi

Keywordsi

Molecular functionDevelopmental protein, G-protein coupled receptor, Receptor, Transducer
Biological processWnt signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-373080 Class B/2 (Secretin family receptors)
R-HSA-4086398 Ca2+ pathway
R-HSA-4086400 PCP/CE pathway
R-HSA-4641263 Regulation of FZD by ubiquitination
R-HSA-5340588 RNF mutants show enhanced WNT signaling and proliferation
SIGNORiO60353

Names & Taxonomyi

Protein namesi
Recommended name:
Frizzled-6
Short name:
Fz-6
Short name:
hFz6
Gene namesi
Name:FZD6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 8

Organism-specific databases

EuPathDBiHostDB:ENSG00000164930.11
HGNCiHGNC:4044 FZD6
MIMi603409 gene
neXtProtiNX_O60353

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini19 – 201ExtracellularSequence analysisAdd BLAST183
Transmembranei202 – 222Helical; Name=1Sequence analysisAdd BLAST21
Topological domaini223 – 233CytoplasmicSequence analysisAdd BLAST11
Transmembranei234 – 254Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini255 – 284ExtracellularSequence analysisAdd BLAST30
Transmembranei285 – 305Helical; Name=3Sequence analysisAdd BLAST21
Topological domaini306 – 324CytoplasmicSequence analysisAdd BLAST19
Transmembranei325 – 345Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini346 – 370ExtracellularSequence analysisAdd BLAST25
Transmembranei371 – 391Helical; Name=5Sequence analysisAdd BLAST21
Topological domaini392 – 416CytoplasmicSequence analysisAdd BLAST25
Transmembranei417 – 437Helical; Name=6Sequence analysisAdd BLAST21
Topological domaini438 – 473ExtracellularSequence analysisAdd BLAST36
Transmembranei474 – 494Helical; Name=7Sequence analysisAdd BLAST21
Topological domaini495 – 706CytoplasmicSequence analysisAdd BLAST212

Keywords - Cellular componenti

Cell membrane, Cytoplasmic vesicle, Membrane

Pathology & Biotechi

Involvement in diseasei

Nail disorder, non-syndromic congenital, 10 (NDNC10)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA nail disorder characterized by a variable degree of onychauxis (thick nails), hyponychia, and onycholysis of all nails, with claw-shaped fingernails in some individuals. No other anomalies of ectodermal tissues, including hair, teeth, sweat glands, or skin, are noted, and individuals with dysplastic nails have normal hearing and normal psychomotor development.
See also OMIM:614157
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_066398511R → C in NDNC10; also found in a patient with neural tube defects; the mutant protein localizes to the lysosomes compared to wild-type. 2 PublicationsCorresponds to variant dbSNP:rs151339003EnsemblClinVar.1
Rare non-synonymous variants in FZD6 may contribute to neural tube defects, congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy.

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi8323
MalaCardsiFZD6
MIMi614157 phenotype
OpenTargetsiENSG00000164930
Orphaneti280654 Autosomal recessive nail dysplasia
PharmGKBiPA28461

Polymorphism and mutation databases

BioMutaiFZD6

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 18Sequence analysisAdd BLAST18
ChainiPRO_000001299419 – 706Frizzled-6Add BLAST688

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi24 ↔ 85PROSITE-ProRule annotation
Disulfide bondi32 ↔ 78PROSITE-ProRule annotation
Glycosylationi38N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi69 ↔ 106PROSITE-ProRule annotation
Disulfide bondi95 ↔ 129PROSITE-ProRule annotation
Disulfide bondi99 ↔ 123PROSITE-ProRule annotation
Glycosylationi352N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei653PhosphoserineBy similarity1

Post-translational modificationi

Ubiquitinated by ZNRF3, leading to its degradation by the proteasome.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiO60353
MaxQBiO60353
PaxDbiO60353
PeptideAtlasiO60353
PRIDEiO60353
ProteomicsDBi49378

PTM databases

CarbonylDBiO60353
iPTMnetiO60353
PhosphoSitePlusiO60353
SwissPalmiO60353

Expressioni

Tissue specificityi

Detected in adult heart, brain, placenta, lung, liver, skeletal muscle, kidney, pancreas, thymus, prostate, testis, ovary, small intestine and colon. In the fetus, expressed in brain, lung, liver and kidney.

Gene expression databases

BgeeiENSG00000164930
CleanExiHS_FZD6
ExpressionAtlasiO60353 baseline and differential
GenevisibleiO60353 HS

Organism-specific databases

HPAiHPA017991

Interactioni

Binary interactionsi

Show more details

GO - Molecular functioni

  • ubiquitin protein ligase binding Source: UniProtKB
  • Wnt-protein binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi113919, 17 interactors
DIPiDIP-59893N
IntActiO60353, 12 interactors
MINTiO60353
STRINGi9606.ENSP00000351605

Structurei

3D structure databases

ProteinModelPortaliO60353
SMRiO60353
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini19 – 132FZPROSITE-ProRule annotationAdd BLAST114

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi498 – 503Lys-Thr-X-X-X-Trp motif, mediates interaction with the PDZ domain of Dvl family membersBy similarity6

Domaini

Lys-Thr-X-X-X-Trp motif interacts with the PDZ domain of Dvl (Disheveled) family members and is involved in the activation of the Wnt/beta-catenin signaling pathway.By similarity
The FZ domain is involved in binding with Wnt ligands.By similarity

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3577 Eukaryota
ENOG410XRC8 LUCA
GeneTreeiENSGT00760000118864
HOGENOMiHOG000233237
HOVERGENiHBG006977
InParanoidiO60353
KOiK02376
OMAiCPNMYFK
OrthoDBiEOG091G0N5M
PhylomeDBiO60353
TreeFamiTF317907

Family and domain databases

Gene3Di1.10.2000.10, 1 hit
InterProiView protein in InterPro
IPR015526 Frizzled/SFRP
IPR000539 Frizzled/Smoothened_TM
IPR020067 Frizzled_dom
IPR036790 Frizzled_dom_sf
IPR026543 FZD6
IPR017981 GPCR_2-like
PANTHERiPTHR11309 PTHR11309, 1 hit
PTHR11309:SF75 PTHR11309:SF75, 1 hit
PfamiView protein in Pfam
PF01534 Frizzled, 1 hit
PF01392 Fz, 1 hit
PRINTSiPR00489 FRIZZLED
SMARTiView protein in SMART
SM00063 FRI, 1 hit
SM01330 Frizzled, 1 hit
SUPFAMiSSF63501 SSF63501, 1 hit
PROSITEiView protein in PROSITE
PS50038 FZ, 1 hit
PS50261 G_PROTEIN_RECEP_F2_4, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: O60353-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MEMFTFLLTC IFLPLLRGHS LFTCEPITVP RCMKMAYNMT FFPNLMGHYD
60 70 80 90 100
QSIAAVEMEH FLPLANLECS PNIETFLCKA FVPTCIEQIH VVPPCRKLCE
110 120 130 140 150
KVYSDCKKLI DTFGIRWPEE LECDRLQYCD ETVPVTFDPH TEFLGPQKKT
160 170 180 190 200
EQVQRDIGFW CPRHLKTSGG QGYKFLGIDQ CAPPCPNMYF KSDELEFAKS
210 220 230 240 250
FIGTVSIFCL CATLFTFLTF LIDVRRFRYP ERPIIYYSVC YSIVSLMYFI
260 270 280 290 300
GFLLGDSTAC NKADEKLELG DTVVLGSQNK ACTVLFMLLY FFTMAGTVWW
310 320 330 340 350
VILTITWFLA AGRKWSCEAI EQKAVWFHAV AWGTPGFLTV MLLAMNKVEG
360 370 380 390 400
DNISGVCFVG LYDLDASRYF VLLPLCLCVF VGLSLLLAGI ISLNHVRQVI
410 420 430 440 450
QHDGRNQEKL KKFMIRIGVF SGLYLVPLVT LLGCYVYEQV NRITWEITWV
460 470 480 490 500
SDHCRQYHIP CPYQAKAKAR PELALFMIKY LMTLIVGISA VFWVGSKKTC
510 520 530 540 550
TEWAGFFKRN RKRDPISESR RVLQESCEFF LKHNSKVKHK KKHYKPSSHK
560 570 580 590 600
LKVISKSMGT STGATANHGT SAVAITSHDY LGQETLTEIQ TSPETSMREV
610 620 630 640 650
KADGASTPRL REQDCGEPAS PAASISRLSG EQVDGKGQAG SVSESARSEG
660 670 680 690 700
RISPKSDITD TGLAQSNNLQ VPSSSEPSSL KGSTSLLVHP VSGVRKEQGG

GCHSDT
Length:706
Mass (Da):79,292
Last modified:November 25, 2008 - v2
Checksum:iFBFF5844D6AB0223
GO
Isoform 2 (identifier: O60353-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-32: Missing.

Show »
Length:674
Mass (Da):75,579
Checksum:i43860DD6918CBBCD
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04744033M → V2 PublicationsCorresponds to variant dbSNP:rs827528Ensembl.1
Natural variantiVAR_066963140H → Y1 PublicationCorresponds to variant dbSNP:rs80216383Ensembl.1
Natural variantiVAR_066964152Q → E1 PublicationCorresponds to variant dbSNP:rs61753730Ensembl.1
Natural variantiVAR_047441345M → L4 PublicationsCorresponds to variant dbSNP:rs3808553Ensembl.1
Natural variantiVAR_066965388A → D1 PublicationCorresponds to variant dbSNP:rs142694816Ensembl.1
Natural variantiVAR_066966405R → Q1 PublicationCorresponds to variant dbSNP:rs150760762Ensembl.1
Natural variantiVAR_066398511R → C in NDNC10; also found in a patient with neural tube defects; the mutant protein localizes to the lysosomes compared to wild-type. 2 PublicationsCorresponds to variant dbSNP:rs151339003EnsemblClinVar.1
Natural variantiVAR_066967511R → H in a patient with neural tube defects. 1 PublicationCorresponds to variant dbSNP:rs767273753Ensembl.1
Natural variantiVAR_066968604G → R1 PublicationCorresponds to variant dbSNP:rs79408516Ensembl.1
Natural variantiVAR_066969620S → T1 PublicationCorresponds to variant dbSNP:rs116195528Ensembl.1
Natural variantiVAR_047442664A → E1 PublicationCorresponds to variant dbSNP:rs12549394Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0442911 – 32Missing in isoform 2. 1 PublicationAdd BLAST32

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AB012911 mRNA Translation: BAA25686.1
AF072873 mRNA Translation: AAD41637.1
AF363578 Genomic DNA Translation: AAL50384.1
AB065702 Genomic DNA Translation: BAC05925.1
AK299341 mRNA Translation: BAG61342.1
BX640609 mRNA Translation: CAE45715.1
AC025370 Genomic DNA No translation available.
CH471060 Genomic DNA Translation: EAW91867.1
BC060836 mRNA Translation: AAH60836.2
CCDSiCCDS55268.1 [O60353-2]
CCDS6298.1 [O60353-1]
PIRiJE0164
RefSeqiNP_001158087.1, NM_001164615.1 [O60353-1]
NP_001158088.1, NM_001164616.1 [O60353-2]
NP_001304725.1, NM_001317796.1
NP_003497.2, NM_003506.3 [O60353-1]
UniGeneiHs.591863
Hs.676099

Genome annotation databases

EnsembliENST00000358755; ENSP00000351605; ENSG00000164930 [O60353-1]
ENST00000522566; ENSP00000429055; ENSG00000164930 [O60353-1]
ENST00000523739; ENSP00000429528; ENSG00000164930 [O60353-2]
GeneIDi8323
KEGGihsa:8323
UCSCiuc003ylh.4 human [O60353-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiFZD6_HUMAN
AccessioniPrimary (citable) accession number: O60353
Secondary accession number(s): B4DRN0
, Q6N0A5, Q6P9C3, Q8WXR9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 5, 2001
Last sequence update: November 25, 2008
Last modified: June 20, 2018
This is version 171 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. Human chromosome 8
    Human chromosome 8: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. SIMILARITY comments
    Index of protein domains and families

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