Palmitoylation cycles and regulation of protein function (Review)

Abstract

The efficacy and success of many cellular processes is dependent on a tight orchestration of proteins trafficking to and from their site(s) of action in a time-controlled fashion. Recently, a dynamic cycle of palmitoylation/de-palmitoylation has been shown to regulate shuttling of several proteins, including the small GTPases H-Ras and N-Ras, and the GABA-synthesizing enzyme GAD65, between the Golgi compartment and either the plasma membrane or synaptic vesicle membranes. These proteins are peripheral membrane proteins that in the depalmitoylated state cycle rapidly on and off the cytosolic face of ER/Golgi membranes. Palmitoylation of one or more cysteines, by a Golgi localized palmitoyl transferase (PAT) results in trapping in Golgi membranes, and sorting to a vesicular pathway in route to the plasma membrane or synaptic vesicles. A depalmitoylation step by an acyl protein thioesterase (APT) releases the protein from membranes in the periphery of the cell resulting in retrograde trafficking back to Golgi membranes by a non-vesicular pathway. The proteins can then enter a new cycle of palmitoylation and depalmitoylation. This inter-compartmental trafficking is orders of magnitude faster than vesicular trafficking. Recent advances in identifying a large family of PATs, their protein substrates, and single PAT mutants with severe phenotypes, reveal their critical importance in development, synaptic transmission, and regulation of signaling cascades. The emerging knowledge of enzymes involved in adding and removing palmitate is that they provide an intricate regulatory network involved in timing of protein function and transport that responds to intracellular and extracellular signals.

Involvement of RARRES3 in the regulation of Wnt proteins acylation and signaling activities in human breast cancer cells

“…14 The reversible, covalent attachment of fatty acids to cysteine residues exerts diverse effects on protein stability, function, trafficking and subcellular localization. 15,16 Thus acylation operates as a switch to regulate protein-membrane-binding affinity and the biological activities of proteins. Acyl moieties serve to drive protein substrates into specific membrane domains to facilitate protein interactions or signal transduction.…”

“…20 In particular, a dynamic palmitoylation cycle has been shown to regulate the shuttling of small GTPase H-Ras between intracellular compartments and either the PM or synaptic vesicle membranes. 15,23 The dynamic acylation cycle can be regulated by different physiological stimuli that contribute to cellular homeostasis and plasticity. 24,25 Attachment of an acyl moiety by protein acyltransferases results in the shifting of protein substrates from endoplasmic reticulum or Golgi apparatus to the PM.…”

Novel Membrane-associated Androgen Receptor Splice Variant Potentiates Proliferative and Survival Responses in Prostate Cancer Cells

“…1D shows that, in the absence of its unique C terminus, AR8 failed to localize to the plasma membrane. Because post-translational modifications such as myristoylation and palmitoylation can regulate the steady-state localization and function of various peripheral membrane proteins, such as Ras family small GTPases and Src family kinases (18,19), we examined whether any amino acid residue in AR8 could be lipidated. A bioinformatic search (20) predicted two cysteine residues, Cys-558 and Cys-560, located in the AR8 C-terminal region as putative palmitoylation sites.…”

Emerging roles for protein S-palmitoylation in Toxoplasma biology

“…Palmitoylation has aroused considerable interest due to its enzymatically reversible nature, its predicted impact on the localisation and stability of its substrates and their interaction with other proteins (Linder and Deschenes, 2007;Baekkeskov and Kanaani, 2009). The best-studied examples are probably the two small GTPase isoforms H-and N-Ras, members of the proto-oncogene family that shuttle between the Golgi apparatus and the plasma membrane (PM) to regulate activity and signalling (Ahearn et al, 2012).…”

“…It is possible that the distinct substrate specificities of APT1 and APT2 are due in part to their differential expression between cell types, although some overlap might exist (Tomatis et al, 2010). The palmitoylation cycle that controls the correct compartmentalisation of H-Ras and N-Ras is the most intensively studied example of an APT1 substrate (Baekkeskov and Kanaani, 2009).…”