Depalmitoylaation

Depalmitoylation is the enzymatic removal of palmitoyl groups from proteins. In many cases, palmitoylation refers to a thioester bond linking a 16-carbon palmitoyl chain to a cysteine residue (S-palmitoylation). This modification is dynamic and reversible, influencing protein hydrophobicity, membrane association, localization, trafficking, stability, and regulation of activity. The balance between palmitoylation and depalmitoylation enables rapid changes in signaling and cellular organization.

Enzymes and mechanisms involved in depalmitoylation include thioesterases that hydrolyze the palmitoyl–protein linkage. Known depalmitoylases include the cytosolic enzymes APT1 (LYPLA1) and APT2 (LYPLA2), as well as lysosomal enzymes PPT1 and PPT2. More recently, members of the ABHD (alpha/beta hydrolase domain) family, such as ABHD17, have been identified as depalmitoylases with substrate specificity for certain neuronal proteins. Palmitoyltransferases of the DHHC family catalyze palmitoylation, creating a dynamic cycle in which palmitoyl groups are repeatedly added and removed as cellular conditions change.

Biological significance of depalmitoylation is broad. It governs the membrane targeting and function of many signaling proteins, including members of the Ras and G-protein families, as well as neuronal scaffolding proteins like PSD-95. Proper cycling of palmitoylation and depalmitoylation is essential for normal development, synaptic function, and cellular signaling; its dysregulation has been linked to cancer, neurodegenerative diseases, and other disorders.

Methods to study depalmitoylation include acyl-biotin exchange (ABE), acyl-resin-assisted capture (acyl-RAC), and mass spectrometry-based approaches, often combined with metabolic labeling using palmitate analogs to identify dynamic depalmitoylation events.