SPalmitoylation

S-palmitoylation is the reversible covalent attachment of the 16-carbon saturated fatty acid palmitate to cysteine residues on proteins via a thioester bond. This lipid modification increases the hydrophobicity of the modified protein and promotes or stabilizes association with membranes, affecting localization, trafficking, stability, and activity.

Catalysis and reversibility: S-palmitoyl acyltransferases of the DHHC family mediate the addition of palmitate to cysteine residues (the DHHC motif is essential for activity). The removal of palmitate is carried out by acyl-protein thioesterases such as APT1, APT2, and related enzymes (e.g., ABHD family), allowing dynamic cycling in response to cellular signals.

Substrates and roles: A wide range of signaling proteins, receptors, and trafficking molecules are palmitoylated. Examples include small GTPases (e.g., Ras family), G protein alpha subunits, and synaptic scaffolding proteins such as PSD-95. Palmitoylation modulates membrane targeting, lipid raft association, subcellular distribution, and interaction with other proteins, thereby influencing signal transduction, trafficking, and synaptic function.

Regulation and biological significance: S-palmitoylation is highly dynamic and can respond rapidly to cellular cues, making it a key regulator in neurons and other tissues. Altered palmitoylation has been linked to diseases including cancer and neurodegenerative disorders, highlighting its importance in cellular physiology.

Detection and study: Methods to study palmitoylation include acyl-biotin exchange (ABE), acyl-resin-assisted capture (Acyl-RAC), and metabolic labeling with palmitate analogs followed by click chemistry. Advances in proteomics have expanded the catalog of palmitoylated proteins.