Dishevelled drives Wnt-stimulated disassembly of primary cilia through a unique PDZ-mediated binding mode with Daple and Girdin
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 {beta}-catenin or other non-canonical effectors remain unclear. Its PDZ domain is dispensable for signaling to {beta}-catenin but essential for multiple non-canonical Wnt responses in Drosophila and vertebrate systems. 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 deletions of these motifs or their cognate PDZ domain of DVL2 resulted in elongated primary cilia and rendered these cilia unresponsive to Wnt5a-stimulated disassembly following serum starvation. We conclude that an unprecedented molecular interaction between Dishevelled and Daple or Girdin-L underpins the disassembly of these ciliary organelles with universal links to signaling and cell cycle progression. One-sentence summaryThe PDZ domain of Dishevelled engages in unique interactions with the C-termini of Daple or Girdin-L to mediate the disassembly of primary cilia in response to Wnt5a.