Palmitoylation of G-protein-coupled receptors: a dynamic modification with functional consequences.

Introduction In recent years, covalent modification of proteins by lipi'ds has been found to be a more frequent modification than originally anticipated [ 11. Three major classes of such modifications have been particularly well characterized. These are: (a) the N-terminal myristoylation of glycine residues through amide linkage; (b) the prenylation of cysteine residues, located in C-terminal domains, via the formation of thioether links to farnesyl or geranylgeranyl moieties; and (c) the palmitoylation which occurs through the thioesterification of cysteine residues, located in various domains of proteins, with palmitic acid. In contrast to myristylation and prenylation, which typically occur cotranslationally, palmitoylation is a genuine post-translational modification which can undergo dynamic regulation and which, in some cases, can be modulated by external stimuli [2-41. This modification has been found to be particularly prevalent for proteins involved in processes such as cell adhesion, cell growth and signal transduction, raising the intriguing possibility that it could play regulatory roles in these processes. Palmitoylated proteins include p2 1 rds [ 51, GAP-43 [ 61, several tyrosine kinases belonging to the p60"" family such as p56"" [7], p59'Y", pSS'gr and ~ 5 6 ' " ~ [8], as well as many G-protein a-subunits [9]. For these proteins, the attachment of the 16-carbon-long fatty acid has been proposed to be essential for their targeting to the inner face of the plasma membrane, the site of their biological functions [ 10-131. However, the observation that integral membrane proteins, which