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

Strakova K, Matricon P, Yokota C, Arthofer E, Bernatik O, Rodriguez D, Arenas E, Carlsson J, Bryja V, Schulte G

Cell. Signal. 38 (-) 85-96 [2017-10-00; online 2017-06-29]

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.

Affiliated researcher

Jens Carlsson

SciLifeLab Fellow

PubMed 28668722

DOI 10.1016/j.cellsig.2017.06.018

Crossref 10.1016/j.cellsig.2017.06.018

pii: S0898-6568(17)30176-6

Publications 9.5.0