Publication details
A Wnt-induced conformational phospho-switch in DVL3 controls association with Frizzled receptors and Wnt/β-catenin signaling
| Authors | |
|---|---|
| Year of publication | 2026 |
| Type | Peer-reviewed scientific article |
| Magazine / Source | SCIENCE ADVANCES |
| MU Faculty or unit | |
| Citation | |
| web | https://www.science.org/doi/10.1126/sciadv.aed8899#acknowledgments |
| Doi | https://doi.org/10.1126/sciadv.aed8899 |
| Keywords | DISHEVELLED DEP DOMAIN; PLASMA-MEMBRANE; MULTISITE PHOSPHORYLATION; PROTEIN INTERACTIONS; CANONICAL WNT; DIX DOMAIN; AXIN; PATHWAY; IDENTIFICATION; MECHANISM |
| Attached files | |
| Description | It is well known that Dishevelled (DVL) phosphorylation by casein kinase 1 (CK1) relays Wnt signals from Frizzled (FZD) receptors to downstream effectors, yet any mechanistic aspects of DVL function related to phosphorylation remain unresolved. Here, we uncovered a Wnt-induced DVL phospho-switch that is mutually exclusive with FZD association. CK1 multiphosphorylation changes dramatically the bulk electrostatics to promote DVL intramolecular interaction between the DEP domain and the adjacent disordered region. A panel of DVL3 mutants demonstrated a switch-like behavior at the molecular level when a charge threshold was reached. Charge accumulation proximal to DEP proved to be a key functional event required, but not sufficient, for Wnt/beta-catenin signaling. Proximity interactomics revealed FZD receptors as the prominent effectors of the DVL phospho-switch function consistent with the molecular competition at the DEP interface. By integrating findings at different levels, we propose a universal mechanism, in which Wnt-induced DVL conformational phospho-switch attenuates coresidence with FZDs as a means for downstream signaling events. |
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