In palmitoylation, a palmitoyl group (derived from
palmitic acid, pictured above) is added.Palmitoylation of a cysteine residueLeft Palmitoylation (red) anchors
Ankyrin G to the plasma membrane. Right Close up. Palmityl residue in yellow.Palmitoylation of
Gephyrin Controls Receptor Clustering and Plasticity of GABAergic Synapses[1]
Palmitoylation is the covalent attachment of
fatty acids, such as
palmitic acid, to
cysteine (S-palmitoylation) and less frequently to
serine and
threonine (O-palmitoylation) residues of proteins, which are typically
membrane proteins.[2] The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments,[3] as well as in modulating
protein–protein interactions.[4] In contrast to
prenylation and
myristoylation, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a
thioester bond). The reverse reaction in
mammalian cells is catalyzed by
acyl-protein thioesterases (APTs) in the
cytosol and
palmitoyl protein thioesterases in
lysosomes. Because palmitoylation is a dynamic, post-translational process, it is believed to be employed by the cell to alter the subcellular localization, protein–protein interactions, or binding capacities of a protein.
An example of a protein that undergoes palmitoylation is
hemagglutinin, a membrane glycoprotein used by
influenza to attach to host cell receptors.[5] The palmitoylation cycles of a wide array of
enzymes have been characterized in the past few years, including
H-Ras,
Gsα, the
β2-adrenergic receptor, and
endothelialnitric oxide synthase (eNOS). In signal transduction via G protein, palmitoylation of the α subunit,
prenylation of the γ subunit, and
myristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor.[6]
Mechanism
S-palmitoylation is generally done by proteins with the
DHHC domain. Exceptions exist in non-enzymatic reactions.
Acyl-protein thioesterase (APT) catalyses the reverse reaction.[7] Other acyl groups such as
stearate (C18:0) or
oleate (C18:1) are also frequently accepted, more so in plant and viral proteins, making S-acylation a more useful name.[8][9]
Several structures of the DHHC domain have been determined using
X-ray crystallography. It contains a linearly-arranged
catalytic triad of Asp153, His154, and Cys156. It runs on a
ping-pong mechanism, where the cysteine attacks the acyl-CoA to form an S-acylated DHHC, and then the acyl group is transferred to the substrate. DHHR enzymes exist, and it (as well as some DHHC enzymes) may use a
ternary complex mechanism instead.[10]
An inhibitor of S-palmitoylation by DHHC is
2-Bromopalmitate (2-BP). 2-BP is a nonspecific inhibitor that also halts many other lipid-processing enzymes.[7]
The palmitoylome
A
meta-analysis of 15 studies produced a compendium of approximately 2,000
mammalian proteins that are palmitoylated. The highest associations of the palmitoylome are with
cancers and disorders of the
nervous system. Approximately 40% of
synaptic proteins were found in the palmitoylome.[11]
Biological function
Substrate presentation
Palmitoylation mediates the affinity of a protein for
lipid rafts and facilitates the clustering of proteins.[12] The clustering can increase the proximity of two molecules. Alternatively, clustering can sequester a protein away from a substrate. For example, palmitoylation of phospholipase D (PLD) sequesters the enzyme away from its substrate phosphatidylcholine. When cholesterol levels decrease or PIP2 levels increase the
palmitate mediated localization is disrupted, the enzyme trafficks to PIP2 where it encounters its substrate and is active by
substrate presentation.[13][14][15]
General Anesthesia
Palmitoylation is necessary for the inactivation of anesthesia inducing potassium channels and the localization of GABAAR in synapses. Anesthetics compete with palmitate in ordered lipids and this release gives rise to a component of
membrane-mediated anesthesia. For example the anesthesia channel TREK-1 is activated by anesthetic displacement from GM1 lipids.[16] The palmitoylation site is specific for palmitate over prenylation, however, the anesthetics appear to compete non-specifically. This non-selective competition of anesthetic with palmitate likely gives rise to rise to the
Myer-Overton correlation.
Synapse formation
Scientists have appreciated the significance of attaching long hydrophobic chains to specific proteins in cell signaling pathways. A good example of its significance is in the clustering of proteins in the synapse. A major mediator of protein clustering in the synapse is the postsynaptic density (95kD) protein
PSD-95. When this protein is palmitoylated it is restricted to the membrane. This restriction to the membrane allows it to bind to and cluster ion channels in the
postsynaptic membrane. Also, in the presynaptic neuron, palmitoylation of
SNAP-25 directs it to partition in the cell membrane [17] and allows the
SNARE complex to dissociate during vesicle fusion. This provides a role for palmitoylation in regulating
neurotransmitter release.[18]
Palmitoylation of
delta catenin seems to coordinate activity-dependent changes in synaptic adhesion molecules, synapse structure, and receptor localizations that are involved in memory formation.[19]
Palmitoylation of
gephyrin has been reported to influence
GABAergic synapses.[1]
^Linder, M.E., "Reversible modification of proteins with thioester-linked fatty acids," Protein Lipidation, F. Tamanoi and D.S. Sigman, eds., pp. 215-40 (San Diego, CA: Academic Press, 2000).
^Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (2005). "An acylation cycle regulates localization and activity of palmitoylated Ras isoforms". Science. 307 (5716): 1746–1752.
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PMID15705808.
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^
abLanyon-Hogg, T., Faronato, M., Serwa, R. A., & Tate, E. W. (2017). Dynamic Protein Acylation: New Substrates, Mechanisms, and Drug Targets. Trends in Biochemical Sciences, 42(7), 566–581. doi:10.1016/j.tibs.2017.04.004
^Rana, MS; Lee, CJ; Banerjee, A (28 February 2019). "The molecular mechanism of DHHC protein acyltransferases". Biochemical Society Transactions. 47 (1): 157–167.
doi:
10.1042/BST20180429.
PMID30559274.
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