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Review
. 2010 Dec 27;191(7):1229-38.
doi: 10.1083/jcb.201008160.

The intracellular dynamic of protein palmitoylation

Christine Salaun  1 , Jennifer Greaves, Luke H Chamberlain
Affiliations
Review

The intracellular dynamic of protein palmitoylation

Christine Salaun et al. J Cell Biol. .

Abstract

S-palmitoylation describes the reversible attachment of fatty acids (predominantly palmitate) onto cysteine residues via a labile thioester bond. This posttranslational modification impacts protein functionality by regulating membrane interactions, intracellular sorting, stability, and membrane micropatterning. Several recent findings have provided a tantalizing insight into the regulation and spatiotemporal dynamics of protein palmitoylation. In mammalian cells, the Golgi has emerged as a possible super-reaction center for the palmitoylation of peripheral membrane proteins, whereas palmitoylation reactions on post-Golgi compartments contribute to the regulation of specific substrates. In addition to palmitoylating and depalmitoylating enzymes, intracellular palmitoylation dynamics may also be controlled through interplay with distinct posttranslational modifications, such as phosphorylation and nitrosylation.

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Figures

Figure 1.
Figure 1.
Regulation of membrane binding and trafficking of peripheral proteins by palmitoylation. (A) Proteins modified with single lipid groups (prenylation or N-myristoylation; green circles) have a weak membrane affinity that allows transient membrane interaction. Palmitoylation by membrane-bound DHHC proteins promotes stable membrane association by kinetic trapping (Shahinian and Silvius, 1995). Note that some peripheral proteins are exclusively palmitoylated, and these proteins were suggested to interact with membranes before palmitoylation by way of an intrinsic weak membrane affinity (Greaves et al., 2008, 2009a). (B) Palmitoylation of Ras-farnesyl by Golgi-localized DHHC proteins leads to a dramatic increase in membrane affinity by kinetic trapping. This increased membrane residency facilitates entry of palmitoylated Ras (red circles) into transport vesicles that deliver it to the plasma membrane. It is possible that palmitoylation also serves to move Ras into cholesterol-rich domains from which Golgi exit vesicles are formed (Patterson et al., 2008). Depalmitoylation of Ras can occur anywhere in the cell, perhaps modulated by Apt1, resulting in membrane release and cytosolic diffusion before repalmitoylation at the Golgi. For simplicity, the figure only depicts depalmitoylation occurring at the plasma membrane. This palmitoylation/depalmitoylation regulation of protein sorting is not specific for Ras proteins and may be a common mechanism underlying the sorting of many peripheral palmitoylated proteins (Kanaani et al., 2008; Tsutsumi et al., 2009; Rocks et al., 2010).
Figure 2.
Figure 2.
Regulation of protein localization by palmitoylation dynamics. The illustration depicts three palmitoylated proteins that have different rates of depalmitoylation. In this context, the term depalmitoylation refers to the complete absence of palmitoyl groups on the protein. Rapid depalmitoylation is associated with an enriched steady-state localization on Golgi membranes. This is achieved by depalmitoylation promoting membrane release and subsequent palmitoylation by Golgi-specific DHHC proteins leading to an accumulation at this compartment. Rapid depalmitoylation prevents excessive accumulation on endosomes via vesicular trafficking from the plasma membrane. In contrast, proteins that have a slower rate of depalmitoylation are maintained on membranes for longer and reach endosomal membranes via the plasma membrane. Note that a slower depalmitoylation rate may be achieved by a relative resistance to thioesterases, and/or the presence of many palmitoylated cysteines, and/or palmitoylation by DHHC proteins beyond the Golgi. All of these situations would limit the amount of the protein in a completely depalmitoylated state. This slower rate of depalmitoylation and membrane release limits the steady-state distribution on Golgi membranes.
Figure 3.
Figure 3.
Interplay between phosphorylation/nitrosylation and palmitoylation. (A) Reciprocal regulation of transmembrane proteins. (1) Negatively charged phosphate group prevents palmitoylation of an adjacent cysteine by blocking membrane interaction. (2) Palmitoylation-mediated membrane association prevents access of protein kinases to an adjacent phosphorylation site. (3) Phosphorylation could alter the depalmitoylation rate of a neighboring cysteine, e.g., by increasing access to a thioesterase enzyme. (B) Phosphorylation of a soluble protein prevents palmitoylation by inhibiting transient membrane interaction. (C, 1) Possible regulatory effects of nitrosylation on palmitoylation. Nitrosylation may prevent palmitoylation by direct competition for cysteine residues. (2) It is also possible that nitrosylation could directly displace palmitate. Note that the examples shown do not illustrate the full range of effects that phosphorylation might have on palmitoylation and vice versa.
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