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Palmitoylation is the covalent attachment of
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s, such as
palmitic acid
Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The Li ...
, to
cysteine (''S''-palmitoylation) and less frequently to
serine and
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COOâ ...
(''O''-palmitoylation) residues of proteins, which are typically
membrane
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...
proteins. 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, as well as in modulating
protein–protein interactions. In contrast to
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
and
myristoylation
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminus, N-terminal glycine residue. Myristic acid is a 14-carbon saturat ...
, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a
thioester
In organic chemistry, thioesters are organosulfur compounds with the functional group . They are analogous to carboxylate esters () with the sulfur in the thioester playing the role of the linking oxygen in the carboxylate ester, as implied by t ...
bond). The reverse reaction in
mammalian
Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
cells is catalyzed by
acyl-protein thioesterases (APTs) in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
and
palmitoyl protein thioesterase
Palmitoyl protein hydrolase/thioesterases is an enzyme (EC 3.1.2.22) that removes thioester-linked fatty acyl groups such as palmitate from modified cysteine residues in proteins or peptides during lysosomal degradation. It catalyzes the reac ...
s in
lysosomes
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
. 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
In molecular biology, hemagglutinins (or ''haemagglutinin'' in British English) (from the Greek , 'blood' + Latin , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the ''Paramyxoviridae'' family. Hemagglutinins ar ...
, a membrane glycoprotein used by
influenza
Influenza, commonly known as "the flu", is an infectious disease caused by influenza viruses. Symptoms range from mild to severe and often include fever, runny nose, sore throat, muscle pain, headache, coughing, and fatigue. These symptoms ...
to attach to host cell receptors. The palmitoylation cycles of a wide array of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s have been characterized in the past few years, including
H-Ras,
Gsα
The Gs alpha subunit (Gαs, Gsα) is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein.
Gsα is the founding ...
, the
β2-adrenergic receptor, and
endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
nitric oxide synthase
Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and p ...
(eNOS). In signal transduction via G protein, palmitoylation of the α subunit,
prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
of the γ subunit, and
myristoylation
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminus, N-terminal glycine residue. Myristic acid is a 14-carbon saturat ...
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.
Mechanism
S-palmitoylation is generally done by proteins with the
DHHC domain. Exceptions exist in non-enzymatic reactions.
Acyl-protein thioesterase
Acyl-protein thioesterases are enzymes that cleave off lipid modifications on proteins, located on the sulfur atom of cysteine residues linked via a thioester bond. Acyl-protein thioesterases are part of the α/β hydrolase superfamily of prote ...
(APT) catalyses the reverse reaction.
[Lanyon-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] Other acyl groups such as
stearate (C18:0) or
oleate
Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish. In chemical terms, oleic acid is classified as a monounsaturated omeg ...
(C18:1) are also frequently accepted, moreso in plant and viral proteins, making S-acylation a more useful name.
Several structures of the DHHC domain have been determined using x-ray crystallography. It contains a linearly-arranged
catalytic triad
A catalytic triad is a set of three coordinated amino acids that can be found in the active site of some enzymes. Catalytic triads are most commonly found in hydrolase and transferase enzymes (e.g. proteases, amidases, esterases, acylases, li ...
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
A ternary complex is a protein complex containing three different molecules that are bound together. In structural biology, ''ternary complex'' can also be used to describe a crystal containing a protein with two small molecules bound, for example ...
mechanism instead.
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.
[
]
The palmitoylome
A meta-analysis
A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
of 15 studies produced a compendium of approximately 2,000 mammalian
Mammals () are a group of vertebrate animals constituting the class (biology), class Mammalia (), characterized by the presence of mammary glands which in Female#Mammalian female, females produce milk for feeding (nursing) their young, a ...
proteins that are palmitoylated. The highest associations of the palmitoylome are with cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s and disorders of the nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
. Approximately 40% of synaptic proteins were found in the palmitoylome.
Biological function
Substrate presentation
Palmitoylation mediates the affinity of a protein for lipid rafts
The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. ...
and facilitates the clustering of proteins. 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
Palmitate mediated localization is a biological process that trafficks a palmitoylated protein to ordered lipid domains.
__TOC__
Biological function
One function is thought to cluster proteins to increase the efficiency of protein-protein int ...
is disrupted, the enzyme trafficks to PIP2 where it encounters its substrate and is active by substrate presentation.
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
PSD-95 (postsynaptic density protein 95) also known as SAP-90 (synapse-associated protein 90) is a protein that in humans is encoded by the ''DLG4'' (discs large homolog 4) gene.
PSD-95 is a member of the membrane-associated guanylate kinase (MA ...
. 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
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous sys ...
membrane. Also, in the presynaptic neuron, palmitoylation of SNAP-25
Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a Target Soluble NSF (''N''-ethylmaleimide-sensitive factor) Attachment Protein Receptor ( t-SNARE) protein encoded by the ''SNAP25'' gene found on chromosome 20p12.2 in humans. SNAP-25 is a com ...
directs it to partition in the cell membrane and allows the SNARE
SNARE proteins – " SNAP REceptor" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells,
and some numbers in plants. The primary role of SNARE proteins is to mediate vesicle f ...
complex to dissociate during vesicle fusion. This provides a role for palmitoylation in regulating neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
release.
Palmitoylation of delta catenin
Delta-1-catenin and Delta-2-catenin are members of a subfamily of proteins with ten Armadillo-repeats. Delta-2-catenin is expressed in the brain where it is important for normal cognitive development. Like beta-catenin and gamma-catenin, delta-c ...
seems to coordinate activity-dependent changes in synaptic adhesion molecules, synapse structure, and receptor localizations that are involved in memory formation.
Palmitoylation of gephyrin
Gephyrin is a protein that in humans is encoded by the ''GPHN'' gene.
This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subu ...
has been reported to influence GABAergic synapses.
See also
* DHHC domain
* Myristoylation
Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminus, N-terminal glycine residue. Myristic acid is a 14-carbon saturat ...
* Myelin proteolipid protein
* Palmitoleoylation
Palmitoleoylation is type of protein lipidation where the monounsaturated fatty acid palmitoleic acid is covalently attached to serine or threonine residues of proteins. Palmitoleoylation appears to play a significant role in trafficking and ta ...
* Prenylation
Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...
References
Further reading
*
*Resh, M. (2006
"Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules"
Sci STK. 359 October 31.
*{{cite journal , vauthors=Linder M, Deschenes R , year = 2007 , title = Palmitoylation: policing protein stability and traffic , journal = Nature Reviews Molecular Cell Biology , volume = 8 , issue = 1, pages = 74–84 , doi=10.1038/nrm2084 , pmid=17183362, s2cid = 26339042
External links
CSS-Palm - Palmitoylation Site Prediction with a Clustering and Scoring Strategy
CKSAAP-Palm
Swisspalm - S-Palmitoylation database
Peripheral membrane proteins
Post-translational modification