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.