STRUCTURE, OCCURRENCE AND BIOLOGY
In 1951, proteins that were soluble in organic solvents such as chloroform-methanol were found in rat brain myelin by Folch and Lees (better known for devising the most common method for lipid extraction), who coined the term ‘proteolipid’. However it was another twenty years before it was shown that these contained covalently bound fatty acids and so differed from the plasma lipoproteins. Such lipid-modified proteins are now known to be widespread in nature with a variety of important functions in animals, plants and bacteria. Proteolipids can be defined as all proteins containing containing covalently bound lipid moieties, including fatty acids, isoprenoids, cholesterol and glycosylphosphatidylinositol. The last of these ('GPI-anchored proteins') are discussed elsewhere in these web pages. The term ‘lipoprotein’ is also used to describe such compounds on occasion, but to avoid confusion this might be better reserved for the non-covalently linked lipid-protein complexes of the type found in plasma.
It is a curious but important fact that the two main types of protein with fatty acid modifications to have been described from eukaryotic organisms contain saturated fatty acid components, i.e. those with only myristoyl and those with predominantly palmitoyl moieties, each with a distinctive type of linkage, amide or thiol ester, respectively. Prenylated lipids contain an isoprenoid group linked via a sulfur atom (thiol ether bond) to the protein.
A further important class of proteolipids contains a linkage to cholesterol in addition to N-palmitoylation, the ‘hedgehog’ signalling proteins, while bacteria contain proteolipids with N-acyl- and S-diacylglycerol groups attached to an N-terminal cysteine.
Modification with lipids occurs after synthesis of the proteins and the effect is to change them from a generally hydrophilic nature to one that is hydrophobic at one end at least, facilitating the interaction with membranes. Protein S-palmitoylation occurs at the membrane surface, while S-prenylation and N-myristoylation are brought about by cytoplasmic enzymes. It is now clear that such modifications are important in determining the activities of proteins and in targeting them to specific subcellular membrane domains, including the rafts or caveolae in plasma membranes. Thus, both myristoylated and palmitoylated proteins are targeted to rafts (as are the GPI-anchored proteins), but prenylated lipids are not. It is significant that many signalling proteins (e.g. receptors, G-proteins, protein tyrosine kinases) and often their substrates are modified by lipids with implications for the relevant signalling events at the cell surface. Many of these proteolipids are related to human disease states and are potential pharmacological targets. For example, deregulation of palmitoylation has been associated with cancer, mental retardation and schizophrenia.
1. N-Myristoylated Proteins
In the N-myristoylated proteins, myristic acid (14:0) specifically, which is a ubiquitous but usually minor component of cellular lipids, is bound to the amino-terminal glycine residue (of a relatively conserved sequence of the protein) via an amide linkage that is relatively stable to hydrolysis. Therefore, N-terminal acylation is believed to be an irreversible modification, although there may be exceptions. These proteolipids constitute a large family of essential eukaryotic and viral proteins with many different functions, and they are located either in the cytosol or in the cytosolic (inner) membrane of cells, or both. The acyl group anchors the protein to the membrane, although simultaneous binding to phospholipids or other membrane constituents is necessary to increase the strength of the interaction.
In vivo, the acyl group as the CoA ester is attached by the action of a specific transferase to the N-terminal glycine of the growing peptide as it begins to emerge from the ribosome, i.e. it is mainly a co-translational rather than a post-translational event. There is an absolute requirement for the N-terminal glycine on the target protein, while amino acid residues two through six are used in substrate recognition. The leader methionine residue is first removed from the nascent peptide chain by a methionine aminopeptidase to expose an N-terminal glycine, before an enzyme myristoyl-CoA:protein N‑myristoyltransferase catalyses the formation of the stable amide bond. The specificity of the reaction is controlled in part by the size of an acyl-CoA binding pocket in the enzyme, though other factors may be involved. In addition, it has become apparent that myristoylation can also occur post-translationally on internal glycine residues and in apoptotic cells, when N-terminal glycine residues are exposed in partially hydrolysed proteins. The latter may have implications for health and disease.
About 150 human proteins are known to be myristoylated, and these include tyrosine kinases. The functions of such proteolipids are steadily being unravelled. They are certainly of critical physiological importance, for example as participants in cellular signalling and in the process of apoptosis (regulated cell death). They are involved in regulating protein activity perhaps by modifying or stabilizing their conformations, by facilitating protein-protein interactions, and in targeting otherwise soluble proteins to the membranes and to appropriate receptors. However, a single N-myristoylation is insufficient to promote membrane association, and further N-myristoylation or N-terminal S-palmitoylation is necessary (see below). Increased levels of N-myristoylation have been observed in certain cancers, and there have been suggestions that this could be a target for therapeutic intervention. Over 300 Arabidopsis proteins are believed to be myristoylated, including many protein kinases, phosphatases and transcription factors. Also, N-myristoyltransferase activity is believed to play a role in infections by viruses, bacteria, fungi and parasitic protozoa, including such diseases as malaria.
Exceptions to these generalities are photoreceptor proteins, which are modified heterogeneously with the uncommon 12:0, 5 14:1 and 5,8-14:2 fatty acids as well as 14:0. N-palmitoylated proteins have also been found, usually where there is a dual lipid modification, for example, the cholesterol-linked hedgehog proteins (see below). In addition, myristoylation occurs on the ε-amine group of internal lysines in interleukin 1α and tumor necrosis factor α. With the latter, different enzymes or iso-enzymes from those for N-terminal myristoylation are involved. Similarly, serine residues may be acylated in certain proteins.
Mass spectrometry is currently a key method for characterization of N-myristoylated proteins, although the fatty acyl group can be released for analysis by conventional chromatographic means (e.g. gas chromatography) by the acidic hydrolysis conditions commonly employed to cleave peptide bonds. For example, treatment with 6M HCl or 2M HCl in 83% methanol at 100°C for several hours is required to release the N-acyl group as the free fatty acid or methyl ester, respectively. New methods involving specific chemical probes are now facilitating detection and analysis of N-myristoylated proteins and other proteolipids.
2. S-Palmitoylated Proteins
In the S-palmitoylated proteins, palmitic acid (16:0) is linked to one or more (up to four) internal cysteine residues via labile high-energy thioester bonds. There are approximately 50 such proteins in yeast to several hundred in mammals. The name is something of a misnomer, as other fatty acids are sometimes present, including 16:1, 18:0 and 18:1. For example, viral proteins are often linked to C18 fatty acids. S-Palmitoylation is also observed in conjunction with N-terminal myristoylation or C-terminal prenylation sites. There does not appear to be any specific peptide target, and palmitoylation is often observed of cysteine-rich motifs on the cytosolic side of transmembrane domains or of cysteines close to the N- or C-termini (in contrast to N-myristoylation and isoprenylation). It is now apparent that protein palmitoylation is essential for intracellular signalling and for the folding, trafficking and function of such disparate proteins as Src-family kinases, Ras family GTPases, G-proteins and G-protein coupled receptors.
The hydrophobic proteolipid protein ('PLP') is the main protein in the myelin of the central nervous system, and was the first of this type to be identified and properly characterized. However, a wide variety of different palmitoylated proteins, with many different functions are now known. For example, fifty different palmitoylated proteins have been identified in the yeast Saccharomyces cerevisiae. These can be grouped into three broad categories - poly-acylated membrane proteins (e.g. some receptors and rhodopsin), mono-acylated membrane proteins (some receptors and viral proteins), and hydrophilic proteins (such as certain protein kinases).
Thio-acylation occurs post-translation of the protein, and is catalysed by specific membrane-bound acyltransferases, although there is some evidence for occasional non-enzymatic palmitoylation. Enzymatic mechanisms predominate and protein acyltransferases were identified definitively first from yeasts and subsequently from mammalian cells. A family of such enzymes (23 in humans humans and a similar number in Arabidopsis) has now been characterized with a conserved cysteine-rich domain containing a distinctive aspartate-histidine-histidine-cysteine (DHHC) motif, which is required for activity. They are membrane proteins with a number of subcellular locations that span the bilayer at least four times with the DHHC domain on the cytosolic face.
The protein transacylases are all palmitoylated spontaneously when incubated with palmitoyl-CoA, suggesting that an auto-palmitoylated acyl-enzyme intermediate is involved in the transfer of the palmitoyl moiety to a substrate. However, an alternative suggestion is that auto-palmitoylation is a regulatory mechanism that facilitates binding of the enzyme to its lipid and protein substrates. There is an absolute requirement for long-chain acyl-CoA esters, mainly 16:0, as fatty acyl donors.
As with the myristoylated proteins, palmitoylation is believed to modify protein function partly by modifying their conformations, but mainly in targeting otherwise soluble proteins to specific membranes or to appropriate receptors. The number of bound fatty acyl groups may control the strength of the interaction with membranes. For example, a hydrophobic protein with a single acylation can bind only loosely to membranes and is easily displaced. However, a second or further acylation ensures strong targeting of a protein to the cytoplasmic face of the membrane, and ensures that it is firmly bound to a specific site on the membrane where an appropriate receptor may be located. Palmitoylation of integral membrane proteins may be a regulatory function, changing their conformation to increase their stability through protecting them from degradation by preventing ubiquitinylation. In addition, palmitoylation is believed to be an important factor in the process of trafficking proteins between organelles and in directing them to specific membrane compartments. For example, in neurons, palmitoylation targets proteins for transport to nerve terminals and may regulate trafficking at synapses. Protein S-palmitoylation is also a basic mechanism for control of the properties and functions of ion channels, both directly and indirectly via other signalling pathways. A further effect of palmitoylation may be to promote certain protein-protein interactions.
More generally, the saturated acyl moiety in palmitoylation facilitates transfer of proteins to lipid rafts, subdomains of the plasma membrane that are enriched in sphingolipids and cholesterol. In this situation, proteolipids can participate in cell signalling events, such as in T-cells of the immune system. In this instance, the unique feature among lipid S-palmitoylation modifications of reversibity is advantageous. For example in lipid rafts, Ras proteins are activated by extracellular stimuli and produce signals that lead to cell proliferation, differentiation and apoptosis. Ras proteins undergo palmitoylation on the Golgi membrane, which enables them to be transported to the plasma membrane where they exert their signalling function. The signal is attenuated by depalmitoylation and thence dissociation from the plasma membrane. Following recaptured by the Golgi, the protein can undergo a new sequence of plasma membrane targeting and signalling. S-palmitoylation of Ras proteins is also important in fungal pathogens.
In addition, palmitoylation is involved in lipoprotein metabolism. Lipoprotein particles containing apolipoprotein B (apoB), such as chylomicrons, very-low-density and low-density lipoproteins, are essential for the transport of triacylglycerols and cholesterol esters in plasma. It has been established that palmitoylation of apoB regulates the biogenesis of the nascent lipoprotein particles that contain this apolipoprotein and may regulate the amount available for lipid transport.
Palmitoylation of viral proteins is essential for their life cycle. Three types of membrane proteins in viruses, including many that are highly pathogenic, are S-acylated, a factor that is important for the immune response. For example, palmitoylated 'spike' proteins are the main transmembrane proteins in the viral envelope, and they are involved in the entry of viruses into cells by catalysing receptor binding and/or membrane fusion. The viroporins are a second group, which are freely expressed in infected cells, but not into virus particle per se to any appreciable extent. They possess one or two membrane-spanning regions, which amongst other functions serve as hydrophilic pores in membranes. A third diverse group of palmitoylated proteins produced by viruses are peripheral membrane proteins in which the fatty acid component simply anchors the modified protein to a membrane. In addition, protein palmitoylation is critical for activity of many other human pathogens, including fungal and bacterial infections. Parasitic protozoa and fungi possess their own palmitoyltransferases, whereas viruses and bacteria utilize the enzymes in their hosts.
The reverse process of hydrolysis of S-palmitoylated proteins occurs readily and is catalysed by thioesterases (in contrast to the irreversible N-myristoylation). Three such deacylases have been characterized to date, designated LYPLA1 (acyl protein thioesterase 1, APT1), LYPLA2 and PPT1 (protein-palmitoyl thioesterase 1)), each with specificities for particular classes of protein conjugates. Thus, most proteolipids of this type undergo cycles of acylation-deacylation, with a half-life that is much shorter than that of the peptide per se. This permits proteins to shuttle between membranes and other cellular compartments, for example between the plasma membrane and Golgi in both directions. The activities of synthetic and hydrolytic enzymes are regulated dynamically by extracellular stimuli, like phosphorylation, and the level of palmitoylation is determined by a finely tuned balance between the activities of these enzymes in specific cellular locations. This is the regulatory mechanism that controls the activities of the relevant proteins. Glycoproteins of viral membrane are exceptions in that they are palmitoylated at or near the cytoplasmic face and then remain palmitoylated.
Although many S-acylated proteins are known to be present in plants, their study lags behind that in animal tissues. However, fertility Ca2+ signalling, movement of potassium ions, and stress signalling are amongst the various reported functions.
Analysis by modern mass spectrometric methods permits location of the acyl group to specific amino acids. In contrast to the N-acylated proteins, the fatty acids are easily released from the thiol linkage by base-catalysed transesterification for analysis by gas chromatography.
3. O-Acylated Proteins/Peptides
In a few proteolipids, serine or threonine residues are acylated, when an O-acyl rather than an S-acyl linkage is formed. The best characterized example is ghrelin, a circulating 28-amino acid peptide hormone, which is octanoylated at a serine residue (third amino acid from the N-terminus. Ghrelin is of particular importance as a hunger-stimulating hormone produced in the human stomach and pancreas, increasing food intake and adiposity. Amongst many other functions, it is a potent stimulator of growth hormone from the anterior pituitary gland. Only the octanoylated protein binds to its specific receptor, and the ghrelin O-acyltransferase (GOAT) is the enzyme that catalyses octanoylation. This is now a target for pharmaceutical intervention in the treatment of the metabolic syndrome.
The family of Wnt proteins are central mediators of animal development, influencing cell proliferation, differentiation and migration. In murine Wnt3a, the most intensively studied form, they are S-palmitoylated on a conserved cysteine residue, but they have a second unusual acyl modification with palmitoleic acid at a conserved serine residue. O-Acylation requires an acyltransferase termed 'Porcupine' and is essential for intracellular trafficking and activity of Wtn proteins. It has become a high-priority target for an anticancer drug.
4. Prenylated Proteins
Prenylated proteins are formed by attachment of isoprenoid lipid units, farnesyl (C15) or geranylgeranyl (C20), via cysteine thio-ether bonds at or near the carboxyl terminus. Such proteins are ubiquitous in mammalian cells, where they can amount to up to 2% of the total proteins, and they are increasingly being found in microorganisms and plants, especially the latter. Isoprenylation is a stable (non-reversible) modification, which targets specific proteins to membranes and aids protein-protein interactions; it is essential for their functions. However, in contrast to the acylated proteins, the bulky branched nature of the lipid moiety of isoprenylated proteins ensures that the latter cannot be incorporated into ordered raft microdomains.
Whether a protein is prenylated is determined by specific amino acid sequence motifs at the carboxyl terminus, principally a CAAX sequence with cysteine (C) attached to one or two aliphatic amino acids (A) then to a variable carboxyl-terminal amino acid residue (X). A single farnesylation is common, but dual geranylgeranyl modifications are often found. Proteins involved in cellular signalling and trafficking pathways are most involved, and the most important of these are probably the Ras super-family (low-molecular weight G-proteins, or guanosine 5’-triphosphate (GTP) hydrolases), which act as molecular switches for many different signal pathways including those controlling cell proliferation, adhesion, apoptosis and migration, and the integrity of the cytoskeleton.
Biosynthesis involves a concerted series of reactions in which the proteins are transported through various cellular organelles, ending mainly but not only at the plasma membrane. Prenylation occurs in the cytoplasm of the cell after synthesis of the protein per se, with farnesyl or geranylgeranyl pyrophosphate as the isoprenoid substrate, each catalysed by its own transferase, i.e. protein farnesyltransferase and protein geranylgeranyl transferase (two types), respectively. The enzymes transfer the isoprenoid group to either one or two cysteine residues near the C-terminus. Cleavage of the terminal tri-peptide (AAX) then occurs in the endoplasmic reticulum via a specific protease, and the new terminal cysteine is enzymically methylated at the carboxyl group with S-adenosyl methionine as the methyl donor.
S-Acylation (palmitoylation) of prenylated proteins can occur also, increasing the affinity for membranes and influencing subcellular targeting. As the second modification is reversible, it may function as part of a control mechanism. After they have been fully processed, these proteolipids have a high affinity for cellular membranes and possess a unique structure at their carboxyl termini, which functions as a specific recognition motif in some protein-protein interactions.
The "Ras" proteins in mammalian cells are farnesylated, while a subfamily of "Rho" proteins are usually geranylgeranylated. As these are involved in the development of cancer, they are the subject of much pharmaceutical interest, focusing especially on the inhibition of the prenylation reaction. In addition, inhibitors of protein farnesyltransferase have been shown to be efficacious in the treatment of protozoal pathogens and other parasitic diseases in animal models. These also appear to be of value in the treatment of viral and fungal infections.
In plants, protein prenylation is required for plant growth, development and environmental responses, including the control of abscisic acid and auxin signalling and for meristem development. For example, at least 250 proteins in Arabidopsis have the CAAX sequence so may be prenylated.
Degradation of prenylated proteins occurs in the lysosomal compartment of the cell and is catalysed by a prenylcysteine lyase, which is a flavin-containing monooxygenase that converts prenylcysteine to prenyl aldehyde by a novel mechanism.
5. Proteins Linked Covalently to Cholesterol
Cholesterol is found in covalent linkage to specific proteins, known as the "hedgehog" signalling family of which the best studied is the sonic hedgehog (Shh) group. These are formed post-translationally by attachment of cholesterol via an ester bond to glycine in a highly conserved region of the protein(C-terminus)), while a palmitoyl moiety is attached to a cysteine residue at the N-terminus. They were first found and studied in insects, but they are now known to occur in higher organisms, including vertebrates from fish to humans. Proteins that are functionally analogous but structurally distinct are found in nematodes.
During the biosynthesis of the signalling component, the amino-terminal domain is cleaved from a 45kDa precursor protein at a specific glycine residue by an autocatalytic event, followed by internal proteolysis at a conserved sequence. Cholesterol is then attached to glycine in the carboxy-terminal domain of the new 19 kDa peptide, while the amino-terminal cysteine is palmitoylated, via palmitoyl-CoA and a specific palmitoylacyltransferase, with formation of an amide bond as opposed to a thioester bond as in other proteolipids. Unlike the other lipid-modified proteins discussed above, but like the GPI-anchored proteins, the cholesterol moiety (and the palmitoyl residue) is located in the exoplasmic or exterior leaflet of membranes with the protein component in the extracellular region. The process is regulated both positively and negatively by various oxy-cholesterol derivatives including vitamin D3, and the interactions between sterol biosynthesis and hedgehog signalling are increasingly a focus for research.
The reactions are believed to occur in the endoplasmic reticulum and Golgi, and there must be mechanisms to transport the protein or its active component through the membranes and onwards to other cells, but little is known of how this is accomplished. In insect models, there is evidence that these proteolipids are transported in the form of lipoprotein complexes with the lipid moieties in the phospholipid monolayer that surrounds the core of triacylglycerols (TAG) and cholesterol esters (CE).
Both lipid components are essential for the proper tissue distribution and function of the attached proteins. The cholesterol moiety in particular is required to cause the proteins to form multimeric complexes essential for biological activity, perhaps by targeting them to specific raft domains in membranes. This may also facilitate interaction with other membrane-associated molecules. While the protein moiety lacking cholesterol maintains some of the signalling capacity, loss of palmitoylation abolishes the signalling activity entirely. It appears that that palmitate facilitates the cleavage of the N-terminal amino acid by membrane proteases, facilitating the formation of multimeric complexes and opening up the active sites on the proteins.
Hedgehog proteins are believed to have a major role in signalling during the differentiation of cells in the development of all embryos from Drosophila to humans. Vertebrates, for example, express three hedgehog family proteins designated Sonic (Shh), Indian (Ihh) and Desert (Dhh) hedgehog. They are required for a considerable range of processes, from the control of left-right asymmetry of the body to the specification of individual cell types within the brain and limb development. Aberrant expression and/or signalling of the Shh hedgehog proteins have been implicated in the generation of many human cancers. If further confirmation is needed, this illustrates once more the vital importance of cholesterol in animal tissues.
There are recent suggestions that oxysterols other than cholesterol may link covalently to hedgehog proteins and have distinctive functions.
6. Bacterial Proteolipids
All bacteria contain large numbers of proteins (more than 2000 have been identified) with a unique and distinctive post-translational lipid modification that appears to be essential for their efficient function, and even for their pathogenesis via host-pathogen interactions. The lipid components consist of N-acyl- and S-diacylglycerol groups attached to an N-terminal cysteine, i.e. it contains a thio ether bond. In Mycobacterium bovis, for example, positions sn-1 and 2 of the glycerol moiety are linked to palmitic and tuberculostearic acids, respectively, and either fatty acid can be the N-acyl moiety.
As with other proteolipids, the lipid moieties act as an anchor to hold the protein tightly to a hydrophobic cellular membrane while permitting it to operate in an aqueous environment in such important activities as transport, signalling, adhesion, digestion and growth. They are important constituents of the outer membranes of both Gram-positive and Gram-negative bacteria and like the endotoxins (lipopolysaccharides) of Gram-negative bacteria, they are potent stimulants of the human immune system, eliciting pro-inflammatory immune responses by functioning as ligands for specific receptors. They are thus responsible for much of the virulence of the organisms and have the potential to be used in vaccines.
Improved analytical methods are demonstrating that the lipidation state of bacterial lipoproteins may be more complex than has been assumed, and diacyl-, acetyl- and peptidyl-proteolipids can be present in particular bacterial species in addition to the triacyl forms, depending to some extent on environmental conditions.
In the main secretory pathway, proteins destined to become lipidated have N-terminal signal peptides containing a motif known as a lipobox, which directs them to the lipoprotein biogenesis machinery after transport mainly in an unfolded state. The three fatty acyl groups and the glycerol component responsible for binding to the membrane surface are derived from bacterial phospholipids, especially phosphatidylglycerol. Three enzymes are involved in the biosynthetic pathway. The first attaches the diacylglycerol group from phosphatidylglycerol to the thiol of cysteine, the first amino acid after a signal peptide, in the pro-lipoprotein. A second enzyme then removes the signal peptide, while the third acylates the N-terminal amine group of the modified cysteine with a fatty acid from whatever phospholipid is available. This last step always occurs in Gram-negative bacteria, but is found only rarely in Gram-positive bacteria. Once the lipidation reaction is complete, a specific peptidase cleaves the signal peptide, leaving the cysteine as the new amino-terminal residue of the protein component.
Note that the terms ‘lipoprotein’, ‘lipopeptide’ and ‘proteolipid’ are used interchangeably for these compounds in the literature. As discussed in the Introduction to this document to avoid confusion, I prefer to reserve the term ‘lipoprotein’ for the non-covalently linked protein-lipid complexes in plasma.
Lipopeptides: A number of bacterial species produce lipopeptides of which the best known are probably the glycopeptidolipids from Mycobacteria and surfactin and related molecules from Bacillus subtilis. These are discussed in a separate webpage on this site.
7. Other Proteolipids
N-Terminal acetylation of certain membrane proteins targets them for transfer to the Golgi or lysosomes. In yeasts, a covalent conjugate of phosphatidylethanolamine with a protein designated ‘Atg8’ is involved in the process of autophagy (controlled degradation of cellular components) by promoting the formation of membrane vesicles containing the components to be degraded.
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Further information on bacterial proteolipids is available at a dedicated web site - http://www.mrc-lmb.cam.ac.uk/genomes/dolop/.
James Hutton Institute (and Mylnefield Lipid Analysis), Invergowrie, Dundee (DD2 5DA), Scotland.
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