InterPro domain: IPR036790

The frizzled (fz) domain is an extracellular domain of about 120 amino acids.It was first identified in the alpha-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 [ 1 ]. In addition to these proteins, one or two copies of the fz domain are also found [ 2 , 3 , 4 , 5 , 6 ] in:

• The Frzb family; secreted frizzled-like proteins.
• Smoothened; another 7TM receptor involved in hedgehog signaling.
• Carboxpeptidase Z (CPZ).
• Transmembrane serine protease corin (atrial natriuretic peptide-converting enzyme).
• 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) [ 7 ]. 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 [ 7 ]. The crystal structure of a fz domain shows that it is predominantly alpha-helical with all cysteines forming disulphide bonds. In addition to helical regions, two short beta-strands at the N terminus form a minimal beta-sheet with the second beta sheet passing through a knot created by disulphide bonds [ 7 ].

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 ].

This entry represents the frizzled domain superfamily.

1. 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. J. Biol. Chem. 270, 4705-11
2. The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases. Curr. Biol. 8, R405-6
3. The Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases. Curr. Biol. 8, R407
4. Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases. Protein Sci. 7, 1632-5
5. The frizzled motif: in how many different protein families does it occur? Trends Biochem. Sci. 23, 415-7
6. Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart. J. Biol. Chem. 274, 14926-35
7. Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86-90
8. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225-30
9. The cysteine-rich frizzled domain of Frzb-1 is required and sufficient for modulation of Wnt signaling. Proc. Natl. Acad. Sci. U.S.A. 94, 11196-200