Overview: Protein palmitoylation in the nervous system: Current views and unsolved problems

Abstract

Palmitoylation refers to a dynamic post-translational modification of proteins involving the covalent attachment of long-chain fatty acids to the side chains of cysteine, threonine or serine residues. In recent years, palmitoylation has been identified as a widespread modification of both viral and cellular proteins. Because of its dynamic nature, protein palmitoylation, like phosphorylation, appears to have a crucial role in the functioning of the nervous system. Several important questions regarding the post-translational acylation of cysteine residues in proteins are briefly discussed: (a) What are the molecular mechanisms involved in dynamic acylation? (b) What are the determinants of the fatty acid specificity and the structural requirements of the acceptor proteins? (c) What are the physiological signals regulating this type of protein modification, and (d) What is the biological role(s) of this reaction with respect to the functioning of specific nervous system proteins? We also present the current experimental obstacles that have to be overcome to fully understand the biology of this dynamic modification.

Posttranslational modification of tubulin by palmitoylation: I. In vivo and cell-free studies.

“…1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 Bizzozero et al, 1994). Incubation of palmitoylated tubulin with 1 M neutral hydroxylamine for 2 h at room temperature released approximately 40% of the palmitate.…”

“…In eukaryotes, this modification involves the covalent attachment of the long chain fatty acid palmitate primarily to cysteine residues (for review, see Schlesinger et al, 1993;Bizzozero et al, 1994;Casey, 1995;Milligan et al, 1995). There is no specific type of protein that is palmitoylated.…”

“…Cells often contain both palmitoylated and nonpalmitoylated forms of a protein (Skene and Viraig, 1989). Although palmitoylated proteins are membrane associated (Lui et al, 1993;Bizzozero et al, 1994;Wedegaertner and Bourne, 1994), the nonpalmitoylated forms can be membrane associated or cytosolic (Hancock et al, 1989). Palmitoylation of proteins is reversible leading to the belief that this modification plays a regulatory role in a manner analogous to phosphorylation.…”

Posttranslational modification of tubulin by palmitoylation: II. Identification of sites of palmitoylation.

“…Other studies show that palmitoylated proteins interact with membranes (for review, see Bizzozero et al, 1994b). Thus, it is possible that palmitoylation of tubulin creates a novel species that is capable of direct interaction with membranes.…”

“…Cysteine residues are the primary sites of palmitoylation. However, serine, threonine, and lysine residues may also be palmitoylated (for review, see Bizzozero et al, 1994b;Hackett et al, 1994;Stanley et al, 1994).…”