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PROSITE documentation PDOC50038 [for PROSITE entry PS50038]

Frizzled (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:

                                 +----------------|-------+           |
                                 |                |       |           |
    |    |                            |   |           |         |
    +----|----------------------------|---+           +---------+
'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.

Technical section

PROSITE method (with tools and information) covered by this documentation:

FZ, PS50038; Frizzled (fz) domain profile  (MATRIX)


1AuthorsRehn M., Pihlajaniemi T.
TitleIdentification 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.
SourceJ. Biol. Chem. 270:4705-4711(1995).
PubMed ID7876242

2AuthorsXu Y.K., Nusse R.
TitleThe Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases.
SourceCurr. Biol. 8:R405-R406(1998).
PubMed ID9637908

3AuthorsMasiakowski P., Yancopoulos G.D.
TitleThe Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases.
SourceCurr. Biol. 8:R407-R407(1998).
PubMed ID9637909

4AuthorsSaldanha J., Singh J., Mahadevan D.
TitleIdentification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases.
SourceProtein Sci. 7:1632-1635(1998).
PubMed ID10082384

5AuthorsRehn M., Pihlajaniemi T., Hofmann K., Bucher P.
TitleThe frizzled motif: in how many different protein families does it occur?
SourceTrends Biochem. Sci. 23:415-417(1998).
PubMed ID9852758

6AuthorsYan W., Sheng N., Seto M., Morser J., Wu Q.
TitleCorin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart.
SourceJ. Biol. Chem. 274:14926-14935(1999).
PubMed ID10329693

7AuthorsDann C.E., Hsieh J.-C., Rattner A., Sharma D., Nathans J., Leahy D.J.
TitleInsights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains.
SourceNature 412:86-90(2001).
PubMed ID11452312

8AuthorsBhanot P., Brink M., Samos C.H., Hsieh J.-C., Wang Y., Macke J.P., Andrew D., Nathans J., Nusse R.
TitleA new member of the frizzled family from Drosophila functions as a Wingless receptor.
SourceNature 382:225-230(1996).
PubMed ID8717036

9AuthorsLin K., Wang S., Julius M.A., Kitajewski J., Moos M. Jr., Luyten F.P.
TitleThe cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling.
SourceProc. Natl. Acad. Sci. U.S.A. 94:11196-11200(1997).
PubMed ID9326585

10AuthorsRattner A., Hsieh J.-C., Smallwood P.M., Gilbert D.J., Copeland N.G., Jenkins N.A., Nathans J.
SourceProc. Natl. Acad. Sci. U.S.A. 94:2859-2863(1997).

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