A Semisynthetic Fusicoccane Stabilizes a Protein-Protein Interaction and Enhances the Expression of K+ Channels at the Cell Surface

• The crystal structure of 14-3-3 with the mode-3 motif of TASK was solved
• 14-3-3 binding to the potassium channel TASK is stabilized by fusicoccanes
• The semisynthetic fusicoccane FC-THF is a mode-3 specific 14-3-3/TASK stabilizer
• FC-THF promotes trafficking of TASK to the plasma membrane

SummarySmall-molecule stabilization of protein-protein interactions is an emerging field in chemical biology. We show how fusicoccanes, originally identified as fungal toxins acting on plants, promote the interaction of 14-3-3 proteins with the human potassium channel TASK-3 and present a semisynthetic fusicoccane derivative (FC-THF) that targets the 14-3-3 recognition motif (mode 3) in TASK-3. In the presence of FC-THF, the binding of 14-3-3 proteins to TASK-3 was increased 19-fold and protein crystallography provided the atomic details of the effects of FC-THF on this interaction. We also tested the functional effects of FC-THF on TASK channels heterologously expressed in Xenopus oocytes. Incubation with 10 μM FC-THF was found to promote the transport of TASK channels to the cell membrane, leading to a significantly higher density of channels at the surface membrane and increased potassium current.

Graphical AbstractFigure optionsDownload high-quality image (469 K)Download as PowerPoint slide