ABSTRACT
Palmitoylation is the post-translational modification of proteins with palmitic acid (16-carbon saturated fatty acid) and regulates the membrane targeting, subcellular trafficking and function of proteins [1]. Palmitoylation occurs either through amidelinkage (N-palmitoylation) or thioester linkages (S-palmitoylation). S-palmitoylation occurs on cysteine residues in diverse sequence contexts and is more commonly found in most palmitoylated proteins. Here, the term of protein palmitoylation will mean S-palmitoylation. Protein palmitoylation is the frequent lipid modification of neuronal proteins and modifies many important proteins, including synaptic vesicle proteins, ion channels, guanosine triposphate (GTP)-binding proteins, neurotransmitter receptors and synaptic scaffolding proteins [2]. Examples include PSD-95, a protein that scaffolds receptors and signaling enzymes at the post-synapse; NCAM140, a neural cell adhesion molecule that localizes at the growth cone and regulates neurite outgrowth; and SNAP-25, a t-SNARE protein that regulates neurotransmitter release [2]. PSD-95 palmitoylation is necessary for sorting of PSD-95 to dendrites and participates in the post-synaptic clustering of PSD-95 in dendritic spines, thereby regulating the clustering of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors [3]. Unlike other irreversible lipid modifications such as myristoylation and prenylation, palmitoylation is relatively labile and palmitate on proteins turns over rapidly. Importantly, the specific
extracellular signal regulates protein-palmitoylation levels [4]. At post-synaptic sites, palmitate continuously turns over on PSD-95. Depalmitoylation of PSD-95 is enhanced by glutamate receptor-mediated synaptic activity, and this process dissociates PSD-95 and AMPA receptors from the postsynaptic sites [3].
