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

Jakub Harnoš, Maria Consuelo Alonso Cañizal, Miroslav Jurásek, Jitender Kumar, Cornelia Holler, Alexandra Schambony, Kateřina Hanáková, Ondřej Bernatík, Zbyněk Zdráhal, Kristína Gömöryová, Tomáš Gybeľ, Tomasz Witold Radaszkiewicz, Marek Kravec, Lukáš Trantírek, Jan Ryneš, Zankruti Dave, Ana Iris Fernández-Llamazares, Robert Vácha, Konstantinos Tripsianes, Carsten Hoffmann and Vítězslav Bryja ()
Additional contact information
Jakub Harnoš: Masaryk University
Maria Consuelo Alonso Cañizal: University of Würzburg
Miroslav Jurásek: Masaryk University
Jitender Kumar: Masaryk University
Cornelia Holler: Max Planck Institute for the Science of Light
Alexandra Schambony: Max Planck Institute for the Science of Light
Kateřina Hanáková: Masaryk University
Ondřej Bernatík: Masaryk University
Zbyněk Zdráhal: Masaryk University
Kristína Gömöryová: Masaryk University
Tomáš Gybeľ: Masaryk University
Tomasz Witold Radaszkiewicz: Masaryk University
Marek Kravec: Masaryk University
Lukáš Trantírek: Masaryk University
Jan Ryneš: Masaryk University
Zankruti Dave: Masaryk University
Ana Iris Fernández-Llamazares: Pepscan Therapeutics B.V.
Robert Vácha: Masaryk University
Konstantinos Tripsianes: Masaryk University
Carsten Hoffmann: University of Würzburg
Vítězslav Bryja: Masaryk University

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: Abstract 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 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-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 CK1ɛ in DVL conformational dynamics.

Date: 2019
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DOI: 10.1038/s41467-019-09651-7

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