Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
19  structures 372  species 1  interaction 3182  sequences 26  architectures

Family: Frizzled (PF01534)

Summary: Frizzled/Smoothened family membrane region

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Frizzled". More...

Frizzled Edit Wikipedia article

Frizzled/Smoothened family membrane region
Crystal structure of the cysteine-rich domain of mouse frizzled 8 (mfz8)[1]
Pfam clanGPCR_A
OPM superfamily6
OPM protein4jkv

Frizzled is a family of G protein-coupled receptor proteins[2] that serves as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.

Species distribution

Frizzled proteins and the genes that encode them have been identified in an array of animals, from sponges to humans.[3]


Frizzled proteins also play key roles in governing cell polarity, embryonic development, formation of neural synapses, cell proliferation, and many other processes in developing and adult organisms. These processes occur as a result of one of three signaling pathways. These include the canonical Wnt/β-catenin pathway, Wnt/calcium pathway, and planar cell polarity (PCP) pathway.[3] Mutations in the human frizzled-4 receptor have been linked to familial exudative vitreoretinopathy, a rare disease affecting the retina at the back of the eye, and the vitreous, the clear fluid inside the eye.

The frizzled (fz) locus of Drosophila coordinates the cytoskeletons of epidermal cells, producing a parallel array of cuticular hairs and bristles.[4][5] In fz mutants, the orientation of individual hairs with respect both to their neighbours and to the organism as a whole is altered. In the wild-type wing, all hairs point towards the distal tip.[5]

In the developing wing, Fz has 2 functions: it is required for the proximal-distal transmission of an intracellular polarity signal; and it is required for cells to respond to the polarity signal. Fz produces an mRNA that encodes an integral membrane protein with 7 putative transmembrane (TM) domains. This protein should contain both extracellular and cytoplasmic domains, which could function in the transmission and interpretation of polarity information.[5] This signature is usually found downstream of the Fz domain (InterProIPR000024)

Cysteine-rich domain

Frizzled proteins include cysteine-rich domain that is conserved in diverse proteins, including several receptor tyrosine kinases.[6][7][8] In Drosophila melanogaster, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have in their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. Sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development, include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal-specific kinase (NSK2), and ROR1 and ROR2. The structure of this domain is known and is composed mainly of alpha helices. This domain contains ten conserved cysteines that form five disulphide bridges.

Group members

The following is a list of the ten known human frizzled receptors:

Overview of signal transduction pathways involved in apoptosis.

As a drug target

Vantictumab is a monoclonal antibody against five frizzled receptors that is under development for the treatment of cancer.

See also


  1. ^ PDB: 1IJY​; Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ (July 2001). "Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains". Nature. 412 (6842): 86–90. doi:10.1038/35083601. PMID 11452312.
  2. ^ Malbon CC (2004). "Frizzleds: new members of the superfamily of G-protein-coupled receptors". Front. Biosci. 9: 1048–58. doi:10.2741/1308. PMID 14977528.
  3. ^ a b Huang HC, Klein PS (2004). "The Frizzled family: receptors for multiple signal transduction pathways". Genome Biol. 5 (7): 234. doi:10.1186/gb-2004-5-7-234. PMC 463283. PMID 15239825.
  4. ^ Adler PN, Vinson C, Park WJ, Conover S, Klein L (1990). "Molecular structure of frizzled, a Drosophila tissue polarity gene". Genetics. 126 (2): 401–16. PMC 1204194. PMID 2174014.
  5. ^ a b c Adler PN, Conover S, Vinson CR (1989). "A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains". Nature. 338 (6212): 263–264. doi:10.1038/338263a0. PMID 2493583.
  6. ^ Nusse R, Xu YK (1998). "The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases". Curr. Biol. 8 (12): R405–R406. doi:10.1016/S0960-9822(98)70262-3. PMID 9637908.
  7. ^ Saldanha J, Singh J, Mahadevan D (1998). "Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases". Protein Sci. 7 (7): 1632–1635. doi:10.1002/pro.5560070718. PMC 2144063. PMID 9684897.
  8. ^ Hofmann K, Pihlajaniemi T, Bucher P, Rehn M (1998). "The frizzled motif: in how many different protein families does it occur?". Trends Biochem. Sci. 23 (11): 415–417. doi:10.1016/S0968-0004(98)01290-0. PMID 9852758.

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Frizzled/Smoothened family membrane region Provide feedback

This family contains the membrane spanning region of frizzled and smoothened receptors. This membrane region is predicted to contain seven transmembrane alpha helices. Proteins related to Drosophila frizzled (P18537) are receptors for Wnt (mediating the beta-catenin signalling pathway) [1] but also the planar cell polarity (PCP) pathway and the Wnt/calcium pathway. The predominantly alpha-helical Cys-rich ligand-binding region (CRD) of Frizzled is both necessary and sufficient for Wnt binding [2]. The smoothened receptor mediates hedgehog signalling [3].

Literature references

  1. Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R; , Nature 1996;382:225-230.: A new member of the frizzled family from Drosophila functions as a Wingless receptor. PUBMED:8717036 EPMC:8717036

  2. Huang HC, Klein PS; , Genome Biol 2004;5:234.: The Frizzled family: receptors for multiple signal transduction pathways. PUBMED:15239825 EPMC:15239825

  3. Chen Y, Struhl G; , Development 1998;125:4943-4948.: In vivo evidence that Patched and Smoothened constitute distinct binding and transducing components of a Hedgehog receptor complex. PUBMED:9811578 EPMC:9811578

  4. Rehn M, Pihlajaniemi T, Hofmann K, Bucher P; , Trends Biochem Sci 1998;23:415-417.: The frizzled motif: in how many different protein families does it occur?. PUBMED:9852758 EPMC:9852758

Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000539

This domain is the membrane spanning region of frizzled and smoothened receptors. This membrane region is predicted to contain seven transmembrane alpha helices. Proteins related to Drosophila frizzled (SWISSPROT) are receptors for Wnt (mediating the beta-catenin signalling pathway) [PUBMED:8717036], but also the planar cell polarity (PCP) pathway and the Wnt/calcium pathway. The predominantly alpha-helical Cys-rich ligand-binding region (CRD) of Frizzled is both necessary and sufficient for Wnt binding [PUBMED:15239825]. The smoothened receptor mediates hedgehog signalling [PUBMED:9811578].

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan GPCR_A (CL0192), which has the following description:

This clan contains various seven-transmembrane receptors and related proteins. A major member is Pfam:PF00001, members of which have been considered to be typical members of the rhodopsin superfamily. Many members of this clan are Caenorhabditis proteins, suggesting great expansion of the relevant families in these nematode worms.

The clan contains the following 45 members:

7TM-7TMR_HD 7tm_1 7tm_2 7tm_3 7tm_4 7TM_GPCR_Sra 7TM_GPCR_Srab 7TM_GPCR_Srb 7TM_GPCR_Srbc 7TM_GPCR_Srd 7TM_GPCR_Srh 7TM_GPCR_Sri 7TM_GPCR_Srj 7TM_GPCR_Srsx 7TM_GPCR_Srt 7TM_GPCR_Sru 7TM_GPCR_Srv 7TM_GPCR_Srw 7TM_GPCR_Srx 7TM_GPCR_Srz 7TM_GPCR_Str 7TMR-DISM_7TM Bac_rhodopsin Ceramidase Dicty_CAR DUF1182 DUF3522 DUF621 Frizzled Git3 GpcrRhopsn4 GPR_Gpa2_C Heliorhodopsin HisKA_7TM HlyIII Lung_7-TM_R Ocular_alb Per1 Pombe_5TM Serpentine_r_xa SID-1_RNA_chan Sre Srg TAS2R V1R


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

Representative proteomes UniProt
Jalview View  View  View  View  View  View  View  View   
HTML View  View               
PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

Representative proteomes UniProt

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

Representative proteomes UniProt
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download    
Gzipped Download   Download   Download   Download   Download   Download   Download   Download    

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_949 (release 4.0)
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Bateman A
Number in seed: 86
Number in full: 3182
Average length of the domain: 283.10 aa
Average identity of full alignment: 37 %
Average coverage of the sequence by the domain: 49.29 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.3 22.3
Trusted cut-off 22.3 22.3
Noise cut-off 22.2 22.2
Model length: 323
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

Sunburst controls


Weight segments by...

Change the size of the sunburst


Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls


The tree shows the occurrence of this domain across different species. More...


Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.


There is 1 interaction for this family. More...



For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Frizzled domain has been found. There are 19 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

Loading structure mapping...