The tyrosine Y2502.39 in Frizzled 4 defines a conserved motif important for structural integrity of the receptor and recruitment of Disheveled
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
28668722
DOI
10.1016/j.cellsig.2017.06.018
PII: S0898-6568(17)30176-6
Knihovny.cz E-resources
- Keywords
- DVL2, Disheveled, FZD(4), Frizzled, GNA12, GNA13,
- MeSH
- Amino Acid Motifs MeSH
- Embryo, Nonmammalian metabolism MeSH
- Frizzled Receptors chemistry metabolism MeSH
- HEK293 Cells MeSH
- Heterotrimeric GTP-Binding Proteins metabolism MeSH
- Conserved Sequence * MeSH
- Humans MeSH
- DNA Mutational Analysis MeSH
- Neoplasms metabolism pathology MeSH
- Polymerization MeSH
- Dishevelled Proteins chemistry metabolism MeSH
- Amino Acid Sequence MeSH
- Wnt Signaling Pathway MeSH
- Signal Transduction MeSH
- Molecular Dynamics Simulation MeSH
- Structural Homology, Protein MeSH
- Tyrosine metabolism MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Xenopus laevis embryology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Frizzled Receptors MeSH
- Heterotrimeric GTP-Binding Proteins MeSH
- Dishevelled Proteins MeSH
- Tyrosine MeSH
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.
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