Dishevelled drives disassembly of primary cilia through a unique PDZ-mediated binding mode with Girdin-L

Dishevelled is a pivotal cytoplasmic hub protein that transmits Wnt signals to various cytoplasmic effectors to specify cell fates and behaviors during animal development. The molecular mechanisms by which Dishevelled directs Wnt outputs towards β-catenin or other effectors remain unclear. Its PDZ domain is dispensable for signaling to β-catenin but essential for multiple β-catenin-independent Wnt responses, such as planar cell polarity, in Drosophila and vertebrates. None of its functionally relevant binding partners are known even though a broad range of PDZ-binding ligands have been identified. Here, we combined proximity labeling with structural and biophysical analysis to discover that Daple and its Girdin-L paralog bear unique extended C-terminal PDZ-binding motifs that bind to the PDZ domain of the main human Dishevelled paralog DVL2 with exceptionally high affinity. Assays in HEK293T cells revealed that DVL2 uses its PDZ domain to cluster around the basal bodies of primary cilia and to recruit Girdin to these organelles. Furthermore, the PDZdependent interaction between these proteins promotes their disassembly, a process that is accelerated in response to Wnt5a stimulation. We conclude that Girdin-L is a functionally relevant ligand of the Dishevelled PDZ domain with a key role in promoting the disassembly of these ciliary organelles.