The Physiology of ProteinS-acylation

Abstract

Protein S-acylation, the only fully reversible posttranslational lipid modification of proteins, is emerging as a ubiquitous mechanism to control the properties and function of a diverse array of proteins and consequently physiological processes. S-acylation results from the enzymatic addition of long-chain lipids, most typically palmitate, onto intracellular cysteine residues of soluble and transmembrane proteins via a labile thioester linkage. Addition of lipid results in increases in protein hydrophobicity that can impact on protein structure, assembly, maturation, trafficking, and function. The recent explosion in global S-acylation (palmitoyl) proteomic profiling as a result of improved biochemical tools to assay S-acylation, in conjunction with the recent identification of enzymes that control protein S-acylation and de-acylation, has opened a new vista into the physiological function of S-acylation. This review introduces key features of S-acylation and tools to interrogate this process, and highlights the eclectic array of proteins regulated including membrane receptors, ion channels and transporters, enzymes and kinases, signaling adapters and chaperones, cell adhesion, and structural proteins. We highlight recent findings correlating disruption of S-acylation to pathophysiology and disease and discuss some of the major challenges and opportunities in this rapidly expanding field.

Specific Palmitoyltransferases Associate with and Activate the Epithelial Sodium Channel

“…Although there is no simple consensus sequence for palmitoylation, algorithms predict that more than 50% of human ion channels are palmitoylated (for reviews, see Refs. 22,26,and 27). Published studies have provided evidence for palmitoylation of numerous voltage-gated channels (e.g.…”

“…Cys palmitoylation of soluble and transmembrane proteins is a reversible post-translational modification that increases protein surface hydrophobicity, facilitating interactions with membranes and/or other proteins (22)(23)(24)(25)(26). Although there is no simple consensus sequence for palmitoylation, algorithms predict that more than 50% of human ion channels are palmitoylated (for reviews, see Refs.…”

Molecular characterisation of the adiponectin receptors, AdipoR1 and AdipoR2

“…Having previously reported that CSE of R1 and R2 is around 60% and 20% in quiescent cells 200 we next sought to investigate a role for palmitoylation in modulation of CSE of R1 and R2, given the recognized role of palmitoylation in regulation of receptor trafficking 209 . We used flow cytometry to determine CSE of the receptors expressed transiently in CHO and HEK293 cells as above.…”

“…In the current study we set out to investigate the putative role of a 'housekeeping' PTM, Spalmitoylation, which has been shown to influence the cellular homeostasis and regulation of a variety of proteins and receptors at multiple levels 209,210 . S-palmitoylation is a reversible lipid modification involving the addition of a saturated 16-carbon palmitate moiety to specific cysteines via a thioester linkage that may, like phosphorylation or ubiquitination, act as a switch.…”

“…Palmitoylation of GPCRs commonly occurs on one or more cysteines found 10 to 14 residues following the seventh TMD 211 and has diverse effects including regulation of cellular trafficking and downstream signaling 177,209,210 . Here we demonstrate that R1 and R2 are constitutively palmitoylated and that palmitoylation of a conserved 'canonical' cysteine, 13 amino acids prior to the first TMD, is required for efficient CSE and adiponectin-mediated activation of downstream effectors.…”