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PALMITOYLATED PROTEINS

 

These proteins are the most extensively studied among proteolipids and the first member among them to be identified was the myelin PLP which represents the major component of the myelin proteins (at least 40%). The long-chain fatty acids (R2, mainly C16:0, C18:0 and C18:1) constitute about 2-4% of the PLP dry weight and are covalently bound by thioester linkages to cystein residues (R1).

R1--S--CO--R2

The presence of thioester bonds was demonstrated by in vitro and in vivo acylation (Ross NW et al., J Neurosci Res 1988, 21, 35; Bizzozero OA et al., J Neurochem 1990, 55, 1986).
PLP was shown to be palmitoylated with acyl-CoA by a non-enzymatic mechanism and depalmitoylated by a specific myelin-associated acyltransferase.

The extreme hydrophobicity of PLP is easily explained by a composition of about 50% apolar amino acid residues and a high degree of fatty acid acylation (Weimbs T et al., Biochemistry 1992, 31, 12289).

Besides myelin PLP, several other membrane proteins were shown to be S-palmitoylated. The best known examples are the followings :

- myelin P0 glycoprotein in peripheral nervous system (Bizzozero OA et al., Anal Biochem 1989, 180, 59).
- ligatin in neonatal enterocytes (Jakoi ER et al., J Biol Chem 1987, 262, 1300).
- lung surfactant proteolipid (Stults JT et al., Am J Physiol 1991, 261, L118).
- rhodopsin in retina cells (O'Brien P et al., J Biol Chem 1987, 262, 5210).
- sodium channel polypeptide (Levinson SR et al., Biophys J 1986, 49, 378A).
- P-selectin  in vascular endothelium (Fujimoto T et al., J Biol Chem 1993, 268, 11394).
- band 3 protein in erythrocytes (Okudo K et al. J Biol Chem 1991, 266, 16420).
- hepatic asialoglycoprotein receptor (Zeng FY et al., J Biol Chem 1995, 270, 21382).
- glycoprotein proteolipids from Sindbis virus (Schmidt MFG et al., Proc Natl Acad Sci USA 1979, 76, 1687).

More than 20 proteins modified by covalent palmitic acid were reviewed in 1988 (Olson EN, Prog Lipid Res 1988, 27, 177) and 14 were added in 1994 (Bizzozero OA et al., Neurochem Res 1994, 19, 923).

A phylogenetic conservation of fatty acid acylation was demonstrated in studying brain myelin from amphibians, reptiles, birds and mammals, suggesting a critical role of this post-translational modification for PLP function (Bizzozero OA et al., Neurochem Res 1999, 24, 269). In all species, PLP contains about 3% (w/w) of bound fatty acids, 78% of them being C16:0, C16:1, C18:0 and C18:1. Curiously, hydroxy and branched-chain fatty acids are absent. While discrepancies are found concerning the fatty acid to protein stoichiometry, it is now accepted that no more than 3 moles of fatty acids are bound to one mole of PLP (MW = 25000). Interestingly, PLP appears to be strongly associated in situ with acidic phospholipids, mostly phosphatidylserine. It is estimated that about 15 molecules of phospholipids form a boundary lipid matrix around a molecule of PLP.