The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases

Genes of the frizzled family have been found in many animal species. They encode seven-transmembrane proteins which act as receptors for secreted Wnt glycoproteins (reviewed in [1]). All Frizzled proteins share the following structural similarities: a signal sequence at the amino terminus; a conserved region of 120 amino acids in the extracellular domain containing a motif of 10 invariantly spaced cysteines (called the cysteine-rich domain or CRD); a seven-pass transmembrane region, in which the transmembrane segments are well conserved; and a cytoplasmic domain with little homology among members of the family. The CRD domain has been shown to be necessary and sufficient for Wnt ligand binding to the surface of expressing cells [2]. We performed a database search for the presence of additional proteins containing the CRD motif. A profile of the CRD was made by BLOCK MAKER [3] at the National Center for Biotechnology Information. The cobbler sequences of the blocks were subsequently used to perform a PSI-BLAST search [4] against the non-redundant protein database. By iterating PSI-BLAST twice more, a variety of proteins were found to share the CRD motif with high significance (E < 0.01). An alignment of the Magazine R405