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bioRxiv · 10.1101/2025.09.10.675378

A Wnt-induced conformational phospho-switch in DVL3 controls interaction with Frizzled receptors and Wnt/β-catenin signaling

Micka, M.·Kumar, J.·Paclikova, P.·Hayek, Z.·Hanakova, K.·BECHARA, C.·Plesingerova, H.·Sedo, O.·Del Nero, E.·Gomoryova, K.·Bystry, V.·Gybel, T.·Cihalova, T.·Kravec, M.·Potesil, D.·Zdrahal, Z.·Tripsianes, K.·Bryja, V.
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Abstract

When Wnt ligands bind to Frizzled (FZD) receptors, Dishevelled protein (DVL) gets multiphosphorylated by Casein kinase 1 (CK1). Although, it is well known that DVL phosphorylation relays Wnt signals from receptors to downstream effectors, any mechanistic aspects of DVL function related to phosphorylation remain unresolved. Here, we uncovered a Wnt-induced DVL phospho-switch which is mutually exclusive with FZD engagement. CK1 multiphosphorylation changes dramatically the bulk electrostatics to promote DVL intramolecular coupling between the DEP domain and the adjacent disordered region. A panel of phospho-switch mutants demonstrated a switch-like coupling at the molecular level when a charge threshold is reached. Charge accumulation proximal to DEP proved to be a key functional event required, but not sufficient, for Wnt/{beta}-catenin signaling. Interestingly, the charge-dependent switch-like character of DVL controlled its association with FZD. By integrating findings at different levels, we propose a universal mechanism in which Wnt-induced DVL conformational phospho-switch outcompetes FZD binding and triggers DVL detachment from FZD.

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Micka, M., Kumar, J., Paclikova, P., Hayek, Z., Hanakova, K., BECHARA, C., Plesingerova, H., Sedo, O., Del Nero, E., Gomoryova, K., Bystry, V., Gybel, T., Cihalova, T., Kravec, M., Potesil, D., Zdrahal, Z., Tripsianes, K., Bryja, V.. 2025-09-10. A Wnt-induced conformational phospho-switch in DVL3 controls interaction with Frizzled receptors and Wnt/β-catenin signaling. https://doi.org/10.1101/2025.09.10.675378

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