Figure 6.

Phase separation in Wnt Signaling. (LEFT) Wnt (Purple) can bind to LRP5/6 (single-pass transmembrane receptor) and Frizzled (Fz) receptors (multipass transmembrane receptor) to initiate Wnt signaling. LRP5/6 can bind Axin (Green) while Fz can bind Disheveled (Dvl, Red). These interactions induce the formation of phase-separated clusters on the cell membrane. (RIGHT) Following Wnt binding, phosphorylation of PPPSPxS motifs on LRP5/6 enables binding of Axin via an undefined region of its C-terminus. Disheveled can bind the Fz receptor intracellular tail by its PDZ domain. Polymerization of DIX domains in both Axin and Dvl promote clustering of membrane-associated proteins at Fz and LRP5/6 receptors. Dvl also contains a C-terminal dimerization domain that enhances multivalent interactions within the Wnt signalosome.