Abstract
Abstract
The WNT signaling system is essential for embryonic development, tissue homeostasis and regeneration. Upon the interaction of WNTs as secreted ligands with their transmembrane receptors from the Frizzled (FZD) family, FZDs recruit the main intracellular transducer, the Dishevelled (DVL) proteins. While the molecular details of FZD-DVL coupling are not fully understood, it is known that phosphatidyl-4,5-bisphosphate (PIP2) increases the affinity of FZD to DVL by a bipartite protein (FZD)-protein (DVL) and protein (DVL)-membrane interaction. Using MD simulations, cryo-EM of the FZD6-DEP complex, live cell imaging, genetically encoded biosensors and computational network analysis we extend this model by identifying a conserved PIP2 binding site in a polar cavity of FZDs through which PIP2 acts as a positive allosteric modulator of DVL-mediated WNT signaling.