Depalmitoylation

Depalmitoylation is the enzymatic removal of palmitoyl groups from proteins, reversing the lipid modification known as S-palmitoylation. Palmitoylation is a reversible post-translational modification in which a 16-carbon palmitoyl group is covalently attached to cysteine residues via a thioester bond. Depalmitoylation thus modulates protein association with membranes and subcellular localization, trafficking, stability, and activity.

Enzymes mediating depalmitoylation include acyl-protein thioesterases such as APT1 (LYPLA1) and APT2 (LYPLA2) in the cytosol and at membranes, which remove palmitate from a subset of substrates. Palmitoyl-protein thioesterases PPT1 and PPT2 also catalyze depalmitoylation, with PPT1 localized to lysosomes and PPT2 in endolysosomal compartments. Non-enzymatic hydrolysis of the thioester bond can occur but is typically slower and less regulated. Together, these enzymes support dynamic cycles of palmitoylation and depalmitoylation.

Biological roles: Depalmitoylation regulates signaling by altering membrane targeting and protein interactions. It affects small GTPases such as Ras family proteins, G-protein subunits, and scaffolding proteins like PSD-95, SNAP-25, and others. In neurons, activity-dependent depalmitoylation modulates synaptic strength and trafficking of receptors and channels.

Clinical relevance: Disruptions in depalmitoylation have been linked to diseases, including neurodegenerative conditions and cancer. Mutations in PPT1 cause infantile neuronal ceroid lipofuscinosis (CLN1), a severe lysosomal storage disorder. Because depalmitoylation controls localization and turnover of key signaling proteins, it is a potential target for therapeutic strategies.

Research methods: Studying depalmitoylation employs biochemical assays and proteomics, such as acyl-biotin exchange (ABE), resin-assisted capture, and mass spectrometry, as well as metabolic labeling with palmitate analogs. These tools help identify substrates and measure dynamic turnover.