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 (Y2502.39) in the intracellular loop 1 (IL1) of human FZD4. We have found Y2502.39 to be crucial for DVL2 interaction and DVL2 translocation to the plasma membrane. Mutant FZD4-Y2502.39F, 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 Y2502.39 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 Y2502.39 and H3484.46 plays a role in specifying downstream signaling pathways induced by the receptor.

Department of Biochemistry and Biophysics and Center for Biomembrane Research Stockholm University SE 10691 Stockholm Sweden

Department of Cell and Molecular Biology Science for Life Laboratory Uppsala University SE 75124 Uppsala Sweden

Laboratory of Molecular Neurobiology Department of Medical Biochemistry and Biophysics Karolinska Institutet Scheeleväg 2 17177 Stockholm Sweden

Laboratory of WNT Signaling Institute of Experimental Biology Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic

Laboratory of WNT Signaling Institute of Experimental Biology Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic; Laboratory of Receptor Biology and Signaling Department of Physiology and Pharmacology Karolinska Institutet Nanna Svartz väg 2 17177 Stockholm Sweden

Section on Molecular Signal Transduction Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health 35A Convent Drive MSC 3752 Bethesda MD 20892 3752 USA

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Dishevelled enables casein kinase 1-mediated phosphorylation of Frizzled 6 required for cell membrane localization