Palmitoylation-dependent protein sorting

Abstract

S-palmitoylation is a posttranslational modification that regulates membrane-protein interactions. However, palmitate is more than just a hydrophobic membrane anchor, as many different types of protein are palmitoylated, including transmembrane proteins. Indeed, there is now compelling evidence that palmitoylation plays a key role in regulating various aspects of protein sorting within the cell.

Figure 1.

Palmitoylation-dependent sorting of AMPA receptors and Ras proteins. (A) Palmitoylation of AMPA receptor GluR subunits at transmembrane 2 (TMD2) promotes retention of the receptor in the Golgi, preventing cell surface delivery. When at the cell surface, internalization of AMPA receptors is regulated by interaction with 4.1N. Palmitoylation in the C terminus of GluR subunits inhibits the 4.1N interaction, facilitating internalization of the receptor. The different colors of GluR indicate palmitoylation status: green is unpalmitoylated, red is palmitoylated at TMD2, and blue is palmitoylated at the C terminus. (B) Ras modified by farnesylation (zigzag line) has a weak affinity for Golgi membranes. Subsequent palmitoylation (straight lines) at the Golgi mediates membrane trapping and facilitates Ras trafficking to the PM. At the PM, Ras is depamitoylated, releasing the protein into the cytosol, where it can rebind to Golgi membranes.

Figure 2.

Regulation of membrane interactions by palmitoylation. (A) Membrane “trapping” by palmitoylation. The figure shows a protein with a relatively weak membrane affinity (such as farnesylated Ras) undergoing dynamic exchange between the cytosol and membrane. Subsequent palmitoylation traps the protein at the membrane by increasing the strength of the hydrophobic anchor. (B) Illustration of a potential mechanism whereby palmitoylation of a cysteine residue masks a protein binding site by pulling it into close proximity to the membrane. One possible outcome would be that the palmitoylated protein is now free to traffic to a distinct membrane compartment. (C) Model depicts palmitoylation modifying the lateral distribution of a protein within the membrane. In this instance, the association with thicker membrane domains relieves a hydrophobic mismatch between the hydrophobic part of transmembrane helices (shown in red) and the original membrane domain. The stabilization of the hydrophobic segments may directly allow the protein to traffic, for example, by preventing aggregation, or, alternatively, the association of the protein with distinct membrane domains might drive subsequent sorting. TMD, transmembrane domain. (D) Hydrophobic mismatch of helix 4 is relieved by palmitoylation, which in this instance changes the tilt of the transmembrane domain. This modified membrane association of the protein may facilitate trafficking. Note that the extent of mismatch shown in C and D has been exaggerated for clarity. The relative positions of polar and nonpolar regions of membrane phospholipids are shown for reference.