The tyrosine Y2502.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled

Publication date: October 2017
Source:Cellular Signalling, Volume 38
Author(s): Katerina Strakova, Pierre Matricon, Chika Yokota, Elisa Arthofer, Ondrej Bernatik, David Rodriguez, Ernest Arenas, Jens Carlsson, Vitezslav Bryja, Gunnar Schulte
Frizzleds (FZDs) are unconventional G protein-coupled receptors, which activate diverse intracellular signaling pathways via the phosphoprotein Disheveled (DVL) and heterotrimeric G proteins. The interaction interplay of FZDs with DVL and G proteins is complex, involves different regions of FZD and the potential dynamics are poorly understood. In the present study, we aimed to characterize the function of a highly conserved tyrosine (Y250^2.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y250^2.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y250^2.39F, impaired in DVL2 binding, was defective in both β-catenin-dependent and β-catenin-independent WNT signaling induced in Xenopus laevis embryos. The same mutant maintained interaction with the heterotrimeric G proteins Gα12 and Gα13 and was able to mediate WNT-induced G protein dissociation and G protein-dependent YAP/TAZ signaling. We conclude from modeling and dynamics simulation efforts that Y250^2.39 is important for the structural integrity of the FZD-DVL, but not for the FZD-G protein interface and hypothesize that the interaction network of Y250^2.39 and H348^4.46 plays a role in specifying downstream signaling pathways induced by the receptor.

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