Scientists map how cells activate a key growth signal—opening drug design doors
Researchers discovered how WNT proteins trigger a crucial molecular handshake that activates cell growth and division. The finding reveals dynamic shape-shifting in this interaction, potentially enabling pharmaceutical companies to design more precise drugs for cancer, regenerative medicine, and developmental disorders.
Originaltitel: WNT stimulation induces dynamic conformational changes in the Frizzled-Dishevelled interaction
Frizzleds (FZD 1-10 ) are G protein-coupled receptors containing an extracellular cysteine-rich-domain (CRD) that presents the orthosteric binding site of the 19 mammalian WNTs, the endogenous agonists of FZDs. FZDs signal via a diverse set of effector proteins, of which Dishevelled (DVL1-3) is the most well studied and which acts as a hub for several FZD-mediated signaling pathways. However, the mechanistic details of how FZD-DVL interaction mediate pathway initiation and provide pathway selectivity remain an enigma. Here, we use bioluminescence resonance energy transfer-based assays employing Venus-tagged DVL2 together with NanoLuciferase-tagged FZD 5 to investigate the WNT-3A- and WNT-5A-induced dynamics of the FZD-DVL interaction. Our biophysical assessment suggests that the ligand-induced BRET changes over time originate from conformational dynamics in the FZD 5 -DVL2 complex rather than recruitment dynamics of DVL2 to FZD 5 . Thus, we suggest that extracellular agonist and intracellular transducers could cooperate with each other through allosteric interaction with FZDs in a ternary complex reminiscent of that of classical GPCRs. <h4>One Sentence Summary</h4> Analysis of the interaction of FZD 5 and DVL2 uncovers WNT-induced conformational dynamics of a WNT-FZD 5 -DVL2 complex.