Acylation of proteins has been linked to caveolae localization, presumably due to the direct interaction of acyl chains by intercalation into the organized lipid of caveolae membranes. Site-directed mutational analysis of eNOS acylation shows the role of two-site acylation in caveolae association and regulation of eNOS activation in caveolae . eNOS is myristoylated during post-translational processing and acylated by covalent attachment of fatty acids at the N-terminus and at a specific cysteine. Silencing of each of these acylation sites inhibited eNOS activity to one-tenth of the activity of wild-type eNOS, and silencing of both acylations is synergistic, resulting in one-hundredth of the activity. The loss of acylation resulted in a loss of association of eNOS with caveolae to the same extent as the loss of activity.
Caveolin itself is acylated at three cysteines, and acylation has been shown to be important in the interaction and organization of caveolin and other proteins with caveolae [59,60]. Acylation is also important in the interaction of caveolin-1 with cholesterol in chaperone complexes. Site-directed mutagenesis studies have revealed that two of the three acylation sites - Cys143 and Cys156 - are required for formation and activity of the chaperone complex that delivers cholesterol from the Golgi to caveolae . The third acylation, at Cys133, is essential for the formation and activity of the chaperone complex that internalizes cholesterol ester into cells .
A number of studies have shown that acylation of proteins is a factor in raft association of proteins and in raft signaling. The Src family of protein tyrosine kinases has been found to contain a number of different acyl groups, with stearate and oleate derivatives showing decreased affinity for rafts compared to the myr-istoylated forms . Enzymes have been identified which can de-acylate lipid raft-associated proteins, such as a recently cloned lysophospholipase/acyl thioester-ase . We have observed heterogeneity in the acylation of several caveolin-asso-ciated proteins (unpublished observations). The mechanisms and roles of acyla-tion in the overall organization and dynamics of caveolae are fruitful areas for further exploration.
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