Dishevelled PDZ domain targeting peptides modulate non-canonical Wnt5a/Ror signaling

Dishevelled (Dvl) is a highly conserved scaffolding protein that plays a key role in the non-canonical Wnt signaling pathway. However, the exact mechanisms by which Dvl modulates pathway activation are not fully understood. The C-terminus of Dvl binds intramolecularly to its PDZ domain, stabilizing Dvl in an autoinhibited, closed state. To evaluate the importance of this intramolecular interaction, we used PDZ-binding peptides to disrupt the autoinhibitory binding. We found that these peptides activated non-canonical Wnt5a/Ror signaling. However, this effect was weaker than that of Wnt5a, suggesting that other factors likely contribute to the full signaling response. Additionally, these PDZ-binding peptides affected Wnt5a-induced signaling, suggesting the significance of Dvl's intermolecular interactions in determining signaling outcomes. Given the wide range of intracellular proteins that interact with the Dvl PDZ domain, these proteins can regulate Wnt signaling by controlling the transition from an inactive, closed state to an open, and possibly active, state.