What does S‐palmitoylation do to membrane proteins?

Abstract

S-palmitoylation is post-translational modification, which consists in the addition of a C16 acyl chain to cytosolic cysteines and which is unique amongst lipid modifications in that it is reversible. It can thus, like phosphorylation or ubiquitination, act as a switch. While palmitoylation of soluble proteins allows them to interact with membranes, the consequences of palmitoylation for transmembrane proteins are more enigmatic. We briefly review the current knowledge regarding the enzymes responsible for palmitate addition and removal. We then describe various observed consequences of membrane protein palmitoylation. We propose that the direct effects of palmitoylation on transmembrane proteins, however, might be limited to four non-mutually exclusive mechanistic consequences: alterations in the conformation of transmembrane domains, association with specific membrane domains, controlled interactions with other proteins and controlled interplay with other post-translational modifications.

Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex

“…All PATs contain a zinc finger and common DHHC motif (Asp-His-His-Cys) within the catalytic domain. However, DHHC enzymes show wide diversity at the N-and C-terminal cytosolic domains that participate in protein-protein interactions and regulation of their activity is not well characterized (24). In regards to these issues, our data demonstrate that DHHC6 is regulated by its SH3 domain-dependent interactions with Selk at the ER membrane.…”

“…The addition of palmitate to target proteins differs from the other fatty acid modifications such as prenylation or N-myristoylation in that it is a reversible modification (18). This has led to the notion that palmitoylation serves to regulate protein function in a manner similar to phosphorylation or ubiquitination (24). (Fig.…”

EGF inhibits constitutive internalization and palmitoylation-dependent degradation of membrane-spanning procancer CDCP1 promoting its availability on the cell surface

“…As addition of palmitate affects protein stability (26), these sites were of interest as regulators of EGF-induced increased CDCP1 lifespan. To first address whether CDCP1 is palmitoylated, we used an acyl-biotinyl exchange assay in which palmitoylated cysteines on proteins present within membrane fractions are labelled with biotin then captured using streptavidin beads before detection by Western blot analysis (27,28).…”

“…However, between 12 and 24 h the kinetics of EGF-induced new protein synthesis coupled with the recycling of CDCP1 seen in Figure 3C-D, predominates over the kinetics of palmitoylation-dependent degradation, resulting in much lower levels of palmitoylated CDCP1 relative to total CDCP1. Palmitoylation also regulates protein location within plasma membrane microdomains, promoting association with cholesterol-and sphingolipid-rich regions, called lipid rafts (26).…”

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

“…[8][9][10] The palmitoylation of a protein can affect its interactions with its surrounding membrane lipids and proteins, therefore impacting certain properties such as association with specific membrane domains, trafficking between cell compartments or stability. [11][12][13] The palmitoylation reaction is catalyzed by the conserved DHHC (aspartate-histidine-histidine-cysteine) family of enzymes, which are characterized by the specific DHHC motif required for the palmitoyl acyltransferase (PAT) activity. 14 In human, the 23 members of the DHHC family described are localized to the distinct intracellular membrane compartments, mainly the Golgi apparatus and the endoplasmic reticulum where palmitoylation likely occurs.…”