Summary: Frizzled/Smoothened family membrane region
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Frizzled Edit Wikipedia article
|Frizzled/Smoothened family membrane region|
Crystal structure of the cysteine-rich domain of mouse frizzled 8 (mfz8)
Frizzled is a family of G protein-coupled receptor proteins that serves as receptors in the Wnt signaling pathway and other signaling pathways. When activated, Frizzled leads to activation of Dishevelled in the cytosol.
Frizzled proteins and the genes that encode them have been identified in an array of animals, from sponges to humans.
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/Î²-catenin pathway, Wnt/calcium pathway, and planar cell polarity (PCP) pathway. 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. 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.
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. This signature is usually found downstream of the Fz domain (InterPro: IPR000024)
Frizzled proteins include cysteine-rich domain that is conserved in diverse proteins, including several receptor tyrosine kinases. 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.
The following is a list of the ten known human frizzled receptors:
- Frizzled-1 (FZD1)
- Frizzled-2 (FZD2)
- Frizzled-3 (FZD3)
- Frizzled-4 (FZD4)
- Frizzled-5 (FZD5)
- Frizzled-6 (FZD6)
- Frizzled-7 (FZD7)
- Frizzled-8 (FZD8)
- Frizzled-9 (FZD9)
- Frizzled-10 (FZD10)
As a drug target
- doi:10.1038/35083601. PMID 11452312. ; 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): 86â€“90.
- Malbon CC (2004). "Frizzleds: new members of the superfamily of G-protein-coupled receptors". Front. Biosci. 9: 1048â€“58. doi:10.2741/1308. PMID 14977528.
- 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.
- Adler PN, Vinson C, Park WJ, Conover S, Klein L (1990). "Molecular structure of frizzled, a Drosophila tissue polarity gene". Genetics. 126 (2): 401â€“16. PMC 1204194. PMID 2174014.
- Adler PN, Conover S, Vinson CR (1989). "A Drosophila tissue polarity locus encodes a protein containing seven potential transmembrane domains". Nature. 338 (6212): 263â€“264. doi:10.1038/338263a0. PMID 2493583.
- Nusse R, Xu YK (1998). "The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases". Curr. Biol. 8 (12): R405â€“R406. doi:10.1016/S0960-9822(98)70262-3. PMID 9637908.
- 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): 1632â€“1635. doi:10.1002/pro.5560070718. PMC 2144063. PMID 9684897.
- 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): 415â€“417. doi:10.1016/S0968-0004(98)01290-0. PMID 9852758.
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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)  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 . The smoothened receptor mediates hedgehog signalling .
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
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
Internal database links
|SCOOP:||7tm_1 7tm_2 Dicty_CAR Git3 Ocular_alb|
|Similarity to PfamA using HHSearch:||7tm_2|
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 ].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Biological process||cell surface receptor signaling pathway (GO:0007166)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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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 53 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 Chs7 Dicty_CAR DUF1182 DUF3522 DUF621 Frizzled Git3 GpcrRhopsn4 GPR_Gpa2_C Heliorhodopsin HisKA_7TM HlyIII Lung_7-TM_R MASE3 MASE4 Ocular_alb Per1 Pombe_5TM Serpentine_r_xa SID-1_RNA_chan Solute_trans_a Sre Srg STE3 TAS2R THH1_TOM1-3_dom TMEM187 Tmemb_40 V1R
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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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.
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|Seed source:||Pfam-B_949 (release 4.0)|
|Number in seed:||81|
|Number in full:||4781|
|Average length of the domain:||286.30 aa|
|Average identity of full alignment:||40 %|
|Average coverage of the sequence by the domain:||49.63 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||20|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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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 25 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.
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AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.