Dishevelled-3 conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

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Authors

HARNOŠ Jakub CANIZAL M.C.A. JURÁSEK Miroslav KUMAR Jitender HOLLER Cornelia SCHAMBONY Alexandra HANÁKOVÁ Kateřina BERNATÍK Ondřej ZDRÁHAL Zbyněk GÖMÖRYOVÁ Kristína GYBEĽ Tomáš RADASZKIEWICZ Tomasz Witold KRAVEC Marek TRANTÍREK Lukáš RYNEŠ Jan DAVE Zankruti FERNANDEZ-LLAMAZARES Ana Iris VÁCHA Robert TRIPSIANES Konstantinos HOFFMANN Carsten BRYJA Vítězslav

Year of publication 2019
Type Article in Periodical
Magazine / Source Nature Communications
MU Faculty or unit

Faculty of Science

Citation
Web Full Text
Doi http://dx.doi.org/10.1038/s41467-019-09651-7
Keywords PARTICLE MESH EWALD; BETA-CATENIN; WNT/BETA-CATENIN; DIX DOMAIN; MOLECULAR-DYNAMICS; STRUCTURAL BASIS; PDZ DOMAIN; DEP DOMAIN; G-PROTEIN; WNT
Description Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we develop the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein kinase 1 epsilon (CK1 epsilon) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1 epsilon-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1 epsilon in DVL conformational dynamics.
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