Manu BEN-JOHNY

Engineered depalmitoylases tune ion channel activity and neuronal function

S-Palmitoylation is a crucial post-translational modification that tunes the function and localization of various proteins including ion channel complexes and synaptic proteins. Palmitoylation is a reversible process mediated by zDHHC family of palmitoyl-transferases and acyl-protein thioesterases that attach and excise palmitic groups, respectively. Altered protein palmitoylation has been linked to a wide range of ailments including neurodevelopmental and neurodegenerative diseases. As such, strategies to selectively manipulate protein palmitoylation with enhanced temporal and subcellular precision are highly sought after to both delineate physiological functions and as potential therapeutics. Here, we develop a new approach to manipulate palmitoylation of target proteins by engineering the α/β-hydrolase domain containing protein 17 (ABHD17) with a chemically inducible dimerization. We further demonstrate that this strategy is programmable, allowing selective depalmitoylation in specific organelles and of individual protein complexes. Application of this approach revealed multifaceted modulation of presynaptic voltage-gated calcium channels. Overall, this strategy represents a versatile and powerful method for dissecting the dynamics of protein palmitoylation in live cells, providing valuable insights into their regulation in distinct physiological contexts