The Wnt receptor CRD domain is also found in MuSK and related orphan receptor tyrosine kinases

The receptor tyrosine kinase (RTK) MuSK is part of the receptor complex that initiates neuromuscular junction formation in response to agrin [1–3]. MuSK, as well as the related orphan RTK-like proteins Ror1 and Ror2 [4], and their homologs in lower organisms, have an extracellular region composed of varying combinations of immunoglobulin and Kringle domains, but they all also have a domain defined by a pattern of 10 cysteine residues. We have noticed that the spacing of cysteines, and a number of other amino acids, is shared between this domain and a cysteine-rich domain (CRD) that serves as the ligandbinding portion of the Frizzled (Fz) family of seven-pass transmembrane receptors for the Wnt signaling molecules [5]. As seen in other receptor families, the Wnt-binding domain can also be a part of secreted Frizzled-related proteins (sFRPs) [6]. The Fz CRD-like sequences have also been identified in Smoothened (Smo), as well as in the α1 chain of type XVIII collagen (Col18), and carboxypeptidase Z (CPZ). Smo is the signaling partner in the Sonic hedgehog (Shh) receptor system. Smo is inactivated by unoccupied Patched (Ptc) protein. Binding of Shh to Ptc relieves this inhibition. The similarity between Smo and Fz, including the CRD, prompted a suggestion [7] that the activity of Smo may in addition be modulated by a Wnt-related ligand, though no support for this possibility has been presented. Alternatively, the 10-cysteine domain found in these diverse proteins may be thought of as a general module for protein–protein interactions, evolving in different cases to bind very different counterparts (just like immunoglobulin domains). A computer alignment of the CRDs from representative proteins (Figure 1) shows that the Wntbinding Fz receptors and sFRPs form a distinct group, well separated from the Smo and MuSK/Ror receptors. Thus, determination of the binding specificity of CRDs in these receptors, as well as in Col18 and CPZ, seems likely to reveal new binding capabilities of the 10cysteine module.