{PDOC50038}
{PS50038; FZ}
{BEGIN}
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* Frizzled (fz) domain profile *
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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 (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
alpha-helical with  all  cysteines  forming  disulfide  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 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.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: October 2002 / Text revised.

[ 1] Rehn M., Pihlajaniemi T.
     "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. 270:4705-4711(1995).
     PubMed=7876242
[ 2] Xu Y.K., Nusse R.
     "The Frizzled CRD domain is conserved in diverse proteins including
     several receptor tyrosine kinases."
     Curr. Biol. 8:R405-R406(1998).
     PubMed=9637908
[ 3] Masiakowski P., Yancopoulos G.D.
     "The Wnt receptor CRD domain is also found in MuSK and related orphan
     receptor tyrosine kinases."
     Curr. Biol. 8:R407-R407(1998).
     PubMed=9637909
[ 4] Saldanha J., Singh J., Mahadevan D.
     "Identification of a Frizzled-like cysteine rich domain in the
     extracellular region of developmental receptor tyrosine kinases."
     Protein Sci. 7:1632-1635(1998).
     PubMed=10082384
[ 5] Rehn M., Pihlajaniemi T., Hofmann K., Bucher P.
     "The frizzled motif: in how many different protein families does it
     occur?"
     Trends Biochem. Sci. 23:415-417(1998).
     PubMed=9852758
[ 6] Yan W., Sheng N., Seto M., Morser J., Wu Q.
     "Corin, a mosaic transmembrane serine protease encoded by a novel cDNA
     from human heart."
     J. Biol. Chem. 274:14926-14935(1999).
     PubMed=10329693
[ 7] Dann C.E., Hsieh J.-C., Rattner A., Sharma D., Nathans J., Leahy D.J.
     "Insights into Wnt binding and signalling from the structures of two
     Frizzled cysteine-rich domains."
     Nature 412:86-90(2001).
     PubMed=11452312; DOI=10.1038/35083601
[ 8] Bhanot P., Brink M., Samos C.H., Hsieh J.-C., Wang Y., Macke J.P.,
     Andrew D., Nathans J., Nusse R.
     "A new member of the frizzled family from Drosophila functions as a
     Wingless receptor."
     Nature 382:225-230(1996).
     PubMed=8717036
[ 9] Lin K., Wang S., Julius M.A., Kitajewski J., Moos M. Jr., Luyten F.P.
     "The cysteine-rich frizzled domain of Frzb-1 is required and
     sufficient for modulation of Wnt signaling."
     Proc. Natl. Acad. Sci. U.S.A. 94:11196-11200(1997).
     PubMed=9326585
[10] Rattner A., Hsieh J.-C., Smallwood P.M., Gilbert D.J., Copeland N.G.,
     Jenkins N.A., Nathans J.
     Proc. Natl. Acad. Sci. U.S.A. 94:2859-2863(1997).

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