Journal article
Carl-Fredrik Bowin, P. Kozielewicz, Lukas Grätz, Maria Kowalski-Jahn, Hannes Schihada, G. Schulte
Science Signaling, 2023
Science Signaling, 2023
Semantic Scholar
DOI
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APA
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Bowin, C.-F., Kozielewicz, P., Grätz, L., Kowalski-Jahn, M., Schihada, H., & Schulte, G. (2023). WNT stimulation induces dynamic conformational changes in the Frizzled-Dishevelled interaction. Science Signaling.
Chicago/Turabian
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Bowin, Carl-Fredrik, P. Kozielewicz, Lukas Grätz, Maria Kowalski-Jahn, Hannes Schihada, and G. Schulte. “WNT Stimulation Induces Dynamic Conformational Changes in the Frizzled-Dishevelled Interaction.” Science Signaling (2023).
MLA
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Bowin, Carl-Fredrik, et al. “WNT Stimulation Induces Dynamic Conformational Changes in the Frizzled-Dishevelled Interaction.” Science Signaling, 2023.
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@article{carl-fredrik2023a,
title = {WNT stimulation induces dynamic conformational changes in the Frizzled-Dishevelled interaction},
year = {2023},
journal = {Science Signaling},
author = {Bowin, Carl-Fredrik and Kozielewicz, P. and Grätz, Lukas and Kowalski-Jahn, Maria and Schihada, Hannes and Schulte, G.}
}
Abstract
Frizzleds (FZDs) are G protein–coupled receptors (GPCRs) that bind to WNT family ligands. FZDs signal through multiple effector proteins, including Dishevelled (DVL), which acts as a hub for several downstream signaling pathways. To understand how WNT binding to FZD stimulates intracellular signaling and influences downstream pathway selectivity, we investigated the dynamic changes in the FZD5-DVL2 interaction elicited by WNT-3A and WNT-5A. Ligand-induced changes in bioluminescence resonance energy transfer (BRET) between FZD5 and DVL2 or the isolated FZD-binding DEP domain of DVL2 revealed a composite response consisting of both DVL2 recruitment and conformational dynamics in the FZD5-DVL2 complex. The combination of different BRET paradigms enabled us to identify ligand-dependent conformational dynamics in the FZD5-DVL2 complex and distinguish them from ligand-induced recruitment of DVL2 or DEP to FZD5. The observed agonist-induced conformational changes at the receptor-transducer interface suggest that extracellular agonist and intracellular transducers cooperate through transmembrane allosteric interaction with FZDs in a ternary complex reminiscent of that of classical GPCRs. Description WNT binding triggers rearrangements in a receptor-effector complex that may affect downstream signaling. WNT bends FZD-DVL complexes The binding of WNTs to G protein–coupled receptors (GPCRs) of the FZD family drives the oligomerization of the intracellular protein DVL at the receptor complex. Although the activation of G proteins to GPCRs depends on ligand-induced conformational changes in the receptors, WNT-induced conformational changes in FZD have not been thought to contribute substantially to DVL-mediated signaling because FZD and DVL can interact in the absence of WNT. Using bioluminescence resonance energy transfer (BRET) assays, Bowin et al. confirmed that FZD5 associated with DVL2 or the isolated DEP domain of DVL2 in the absence of WNT and showed that WNT stimulation promoted changes in the conformation of FZD5-DVL2 and FZD5-DEP complexes. These findings suggest that ligand-induced conformational changes in FZD may influence whether downstream signaling proceeds through DVL or G proteins. —AMV
