PROSITE documentation PDOC50038Frizzled (fz) domain profile
The frizzled (fz) domain is an extracellular domain of about 120 amino acids. It was first identified in the α-1 chain of type XVIII collagen and in members of the Frizzled family of seven transmembrane (7TM) proteins which act as receptors for secreted Wingless (Wg)/Wnt glycoproteins (see <PDOC00219>) [1]. In addition to these proteins, one or two copies of the fz domain are also found [2,3,4,5,6] in:
- The frizbee (Frzb) family; secreted frizzled-like proteins.
- Smoothened; another 7TM receptor involved in hedgehog signaling.
- Carboxpeptidase Z (CPZ).
- Transmembrane serine protease corin.
- Two receptor tyrosine kinases (RTKs) subfamilies, the Ror family and the muscle-specific kinase (MuSK) family.
As the fz domain contains 10 cysteines which are largely conserved, it has also been called cysteine-rich domain (CRD) [1]. The fz domain also contains several other highly conserved residues, for example, a basic amino acid follows C6, and a conserved proline residues lies four residues C-terminal to C9 [5]. The crystal structure of a fz domain shows that it is predominantly α-helical with all cysteines forming disulfide bonds. In addition to helical regions, two short β-strands at the N-terminus form a minimal β-sheet with the second β sheet passing through a knot created by disulfide bonds [7].
The schematic representation of the structure of a typical fz domain is shown below:
+-------------------+ +----------------|-------+ | | | | | xxCxxxxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxCxxxCxxxxxxxCxxxCxxxCxxxxxCxxxxxC | | | | | | +----|----------------------------|---+ +---------+ +----------------------------+
'C': conserved cysteine involved in a disulfide bond.
Several fz domains have been shown to be both necessary and sufficient for Wg/Wnt ligand binding, strongly suggesting that the fz domain is a Wg/Wnt interacting domain [8,9,10].
The profile we developed covers the entire fz domain.
Last update:October 2002 / Text revised.
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PROSITE method (with tools and information) covered by this documentation:
1 | Authors | Rehn M. Pihlajaniemi T. |
Title | Identification of three N-terminal ends of type XVIII collagen chains and tissue-specific differences in the expression of the corresponding transcripts. The longest form contains a novel motif homologous to rat and Drosophila frizzled proteins. | |
Source | J. Biol. Chem. 270:4705-4711(1995). | |
PubMed ID | 7876242 |
2 | Authors | Xu Y.K. Nusse R. |
Title | The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases. | |
Source | Curr. Biol. 8:R405-R406(1998). | |
PubMed ID | 9637908 |
3 | Authors | Masiakowski P. Yancopoulos G.D. |
Title | The Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases. | |
Source | Curr. Biol. 8:R407-R407(1998). | |
PubMed ID | 9637909 |
4 | Authors | Saldanha J. Singh J. Mahadevan D. |
Title | Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. | |
Source | Protein Sci. 7:1632-1635(1998). | |
PubMed ID | 10082384 |
5 | Authors | Rehn M. Pihlajaniemi T. Hofmann K. Bucher P. |
Title | The frizzled motif: in how many different protein families does it occur? | |
Source | Trends Biochem. Sci. 23:415-417(1998). | |
PubMed ID | 9852758 |
6 | Authors | Yan W. Sheng N. Seto M. Morser J. Wu Q. |
Title | Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. | |
Source | J. Biol. Chem. 274:14926-14935(1999). | |
PubMed ID | 10329693 |
7 | Authors | Dann C.E. Hsieh J.-C. Rattner A. Sharma D. Nathans J. Leahy D.J. |
Title | Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. | |
Source | Nature 412:86-90(2001). | |
PubMed ID | 11452312 | |
DOI | 10.1038/35083601 |
8 | Authors | Bhanot P. Brink M. Samos C.H. Hsieh J.-C. Wang Y. Macke J.P. Andrew D. Nathans J. Nusse R. |
Title | A new member of the frizzled family from Drosophila functions as a Wingless receptor. | |
Source | Nature 382:225-230(1996). | |
PubMed ID | 8717036 |
9 | Authors | Lin K. Wang S. Julius M.A. Kitajewski J. Moos M. Jr. Luyten F.P. |
Title | The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. | |
Source | Proc. Natl. Acad. Sci. U.S.A. 94:11196-11200(1997). | |
PubMed ID | 9326585 |
10 | Authors | Rattner A. Hsieh J.-C. Smallwood P.M. Gilbert D.J. Copeland N.G. Jenkins N.A. Nathans J. |
Source | Proc. Natl. Acad. Sci. U.S.A. 94:2859-2863(1997). |
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