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  • Review Article
  • Published:

Palmitoylation: policing protein stability and traffic

Key Points

  • Palmitate is a 16-carbon saturated fatty acid that can be post-translationally added to Cys residues of proteins through a reversible thioester linkage.

  • When the modified Cys residue is at the N terminus of a protein, the palmitate moves from the Cys side chain to the free amino group, resulting in the formation of a stable amide linkage of the fatty acid.

  • Palmitate modifies both integral and peripheral membrane proteins, many of which are involved in cellular signalling or membrane trafficking. Characterization of the palmitoylproteome in Saccharomyces cerevisiae expanded the number of palmitoylated proteins identified in yeast from 15 to 50.

  • A family of protein acyltransferases (PATs) that are defined by the presence of a Cys-rich domain with a characteristic Asp-His-His-Cys motif was discovered first in S. cerevisiae and subsequently in mammalian cells. It has been established that this family accounts for most cellular palmitoylation events in yeast.

  • Palmitate can be removed from proteins by thioesterases. A lysosomal thioesterase removes palmitate from peptides during protein degradation. A second cytoplasmic thioesterase has been identified that hydrolyses palmitate from several signalling proteins in vitro, but its role in vivo is unknown.

  • A cycle of palmitoylation and depalmitoylation of Ras proteins in mammalian cells regulates the trafficking of these proteins between intracellular compartments and the plasma membrane. Palmitoylated Ras proteins move between compartments on vesicles, whereas depalmitoylated Ras proteins move rapidly through the cytoplasm in a vesicle-independent manner.

  • Palmitoylation regulates the stability of several integral membrane proteins by preventing their ubiquitylation.

  • Palmitoylation inhibits aggregation of the mutant-huntingtin protein, indicating another protective role for this modification in preventing the formation of intracellular protein aggregates.

Abstract

Palmitate modifies both peripheral and integral membrane proteins and its addition can be permanent or transient, which makes it unique among the lipid modifications of proteins. The presence of palmitate on a protein affects how the protein interacts with lipids and proteins in a membrane compartment, and the reversibility of palmitoylation allows different modes of trafficking between membrane compartments. Here, we review recent studies that have provided insights into the mechanisms that mediate the functional consequences of this versatile modification.

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Figure 1: Fatty acylation of proteins.
Figure 2: The fates of palmitates that are attached to proteins.
Figure 3: An acylation cycle model of subcellular trafficking of H-Ras and N-Ras in mammalian cells.
Figure 4: Model of anthrax-toxin internalization.
Figure 5: Huntingtin palmitoylation.

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Acknowledgements

The authors would like to thank the National Institutes of General Medical Sciences and Neurological Disorders and Stroke and the National Cancer Institute for support.

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Correspondence to Maurine E. Linder.

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DHHC protein acyltransferases and selected substrates (PDF 225 kb)

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DATABASES

Entrez Protein

NP 002102

OMIM

Huntington's disease

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Glossary

Acylation and deacylation

In the context of protein palmitoylation, the addition or removal of a fatty acid that is thioester-linked to a protein.

Palmitoylproteome

The total set of palmitoylated proteins in an organism or cell.

Palmitate

A 16-carbon saturated fatty acid.

Huntingtin

The protein product of the gene that is mutated in Huntington's disease. Huntingtin is a large protein (>350 kDa) with a stretch of Glu residues near the N terminus. In individuals with the disease, the polyglutamine sequence is expanded to more than 40 residues.

Myristate

a 14-carbon saturated fatty acid.

Farnesyl isoprenoid

A polymer of three isoprene units (2-methylbuta-1,3-diene) that is covalently attached to proteins through a thioether linkage to Cys residues. Farnesyl pyrophosphate, the donor molecule of farnesyl isoprenoid, is an intermediate in the cholesterol biosynthetic pathway.

Prenylation

The enzymatic addition of prenyl moieties (farnesyl or geranylgeranyl groups) to a protein as a post-translational modification.

Endomembrane

A membrane-bound organelle that is in the cytoplasm; compartment other than the plasma membrane.

Fluorescence recovery after photobleaching

(FRAP). A technique used to monitor the lateral diffusion of fluorescent molecules in a cell. A small region of a cell is bleached using a laser beam and the recovery of fluorescence intensity in that area is measured over time as unbleached molecules diffuse into the area and bleached molecules move out.

Green fluorescent protein

(GFP). An autofluorescent protein that was originally identified in the jellyfish Aequorea victoria.

Brefeldin A

A fungal macrocylic lactone that inhibits membrane trafficking from the Golgi apparatus.

Class C Vps complex

A complex composed of the protein products of the vacuolar protein sorting-11 (VPS11), VPS16, VPS 18 and VPS33 genes in S. cerevisiae. Mutations in the Class C genes result in strains that lack an organized vacuole structure, and the complex regulates vesicle fusion between the endosome and the vacuole.

Multivesicular body

An organelle of the late endosomal pathway that contains internal vesicles formed by the invagination of the limiting membrane of the endosome.

Oedema factor

(EF). A component of anthrax toxin, EF is a calmodulin-dependent adenylyl cyclase that exerts its toxicity in the cytoplasm by raising levels of cAMP.

Lethal factor

(LF). A component of anthrax toxin, LF is a zinc-dependent metalloprotease that cleaves mitogen-activated protein kinase kinases, thereby interrupting their signalling pathways.

Type I transmembrane proteins

A protein with a single transmembrane domain, with its N terminus exposed to the luminal or extracellular space and its C terminus exposed to the cytoplasm.

Lipid rafts

Cholesterol-rich subdomains of the plasma membrane.

Sumoylation

Covalent addition of a small ubiquitin-related modifier (SUMO) group to a substrate protein.

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Linder, M., Deschenes, R. Palmitoylation: policing protein stability and traffic. Nat Rev Mol Cell Biol 8, 74–84 (2007). https://doi.org/10.1038/nrm2084

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