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.

• MeSH
• aminokyselinové motivy MeSH
• embryo nesavčí metabolismus   MeSH
• frizzled receptory chemie   metabolismus   MeSH
• HEK293 buňky MeSH
• heterotrimerní G-proteiny metabolismus   MeSH
• konzervovaná sekvence * MeSH
• lidé MeSH
• mutační analýza DNA MeSH
• nádory metabolismus   patologie   MeSH
• polymerizace MeSH
• protein dishevelled chemie   metabolismus   MeSH
• sekvence aminokyselin MeSH
• signální dráha Wnt MeSH
• signální transdukce MeSH
• simulace molekulární dynamiky MeSH
• strukturní homologie proteinů MeSH
• tyrosin metabolismus   MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Xenopus laevis embryologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH