LIG_FZD_DVL_PDZ

The Wnt signalling pathway controls diverse events in the cellular organisms ranging from developmental events to homeostasis. There are many critical components in the Wnt pathway that are required for the efficient signal transduction. Dishevelled (Dvl) is among these components and it transduces the signal from frizzleds (FZD) to downstream components of the Wnt pathway. The Dvl also acts as a branch point by transducing the signal into three different cellular routes (Wallingford,2005). In terms of domain composition it consists of three domains viz. DIX, PDZ and DEP. Importantly, it acts as an intracellular scaffold and interacts with numerous partners. The Dvl PDZ domain is responsible for many of these interactions. This domain is highly flexible and can mediate interaction through the typical PDZ binding motif (Gloy,2002) as well as through an internal motif (Zhang,2009), which is present in the case of FZD. The internal motif of FZD lacks a free C-terminus and binds with the PDZ domain of Dvl directly, which enables the latter to transduce the signal from FZD to downstream components of the Wnt pathway (Wong,2003).

Interestingly, the C-terminal cytoplasmic region of all known FZD receptors differs in length and sequence similarity. As a result, all FZD do not bind to Dvl and hence may have distinct function depending on the Wnt ligand they interact with (Umbhauer,2000). Furthermore, the binding affinity varies depending on the Dvl (1-3) - FZD (1-10) pair. The Dvl internal binding motif generally has a consensus sequence pattern of KT...W, which is located two amino acids after the seventh TM helix. This is the minimum region required for the protein interaction and mutations in any of these conserved residues can disrupt the Wnt/β-catenin signalling which signifies the biological function of the motif (Umbhauer,2000).

The same motif is also utilized by other proteins like Idax, which negatively regulate the Wnt pathway (London,2004). The interaction of the Dlg protein with this motif is known to regulate the spindle orientation in the PCP pathway (Garcia,2014).