Glycosylphosphatidylinositol Anchors for Proteins
and Phosphatidylinositol Mannosides
Glycosylphosphatidylinositols are complex glycophospholipids that are found in all eukaryotic organisms, from fungi to plants and animals, and they function to anchor cell proteins to membranes after covalent attachment via the C-termini as post-translational modifications. Glycosylphosphatidylinositol-anchored proteins display many different and important functions, ranging from enzymatic activity, signalling, cell adhesion, cell wall metabolism and immune responses. Their spatio-temporal organization within specific domains of the plasma membrane is crucial for their biological activities in cells.
They were discovered after a novel phospholipase C was obtained from Bacillus cereus in 1976 with the specificity to act upon phosphatidylinositol to generate diacylglycerol and inositol phosphate. When this was tested with tissues a year or two later, it was found to release a variety of proteins including 5’‑nucleotidase and erythrocyte acetylcholinesterase in addition to the expected metabolites. It was apparent that these and many other proteins were covalently attached to phosphatidylinositol located in the cellular membranes. By 1985, detailed evidence was obtained for various components linking phosphatidylinositol to cell surface proteins, especially in relation to acetylcholinesterase in several species and of surface glycoproteins in the parasitic protozoan Trypanosoma brucei, where they were more readily accessible in sufficient quantity for structural analysis (a hundred times greater than in mammalian cells), and by 1988 a complete structure of the last was obtained by M.A.J. Ferguson and colleagues.
As the lipid component of these glycosylphosphatidylinositols linked to proteins is much more complex than in other covalently linked protein-lipid complexes, such as the proteolipids, the latter are discussed in a separate web page. One important difference between the two lipid-protein classes is that the main functional site for glycosylphosphatidylinositol-anchored proteins is on the external surface of the plasma membrane (or in the cell wall of lower organisms), while other proteolipids are located on the cytosolic face of the plasma membrane.
Phosphatidylinositol mannosides are related lipids but with oligosaccharides attached to phosphatidylinositols, which have a function in the surface antigenicity of protozoal parasites and of some prokaryotic organisms, including pathogenic Mycobacteria. In view of the similarities between the basic lipid components, these are also discussed in this web page.
1. Structure and Occurrence of Glycosylphosphatidylinositol-Anchored Proteins
As studies were extended to mammalian systems, it soon became apparent that there was a basic general structure for the lipid component of what became known as the glycosylphosphatidylinositol(GPI)-anchored proteins. Phosphatidylinositol in the external leaflet of the plasma membrane is the lipid anchor that binds a variety of proteins via the C-terminus to a phosphoethanolamine unit at the end of a complex glycosyl bridge to inositol. The basic structure is a post-translational modification that is conserved in eukaryotic organisms, although some molecular aspects such as side chains are variable. These protein-lipid complexes are ubiquitous in eukaryotes (fungi, protozoans, plants, insects and animals) and they have also been shown to be present in some of the Archaebacteria (but not Eubacteria). In animals, they are found in every type of cell and tissue.
A typical molecule is illustrated schematically. These complicated glycophospholipid-protein aggregates are abundant in nature, amounting to about 1% of all proteins and up to 20% of membrane proteins (at least 250 different or 150 in humans), which have very many different functions; they include hydrolytic enzymes, adhesion molecules, receptors, protease inhibitors, and regulatory proteins. Typically, the GPI-protein complexes are widely believed to be associated with the membrane domains known as rafts with a tendency to form homo-dimers. The protein components can be released from the membrane by enzymic cleavage of the protein-lipid bond.
The aliphatic residues are embedded in the membrane, and their chemical composition is dependent on the organism and the stage in its life cycle, but commonly position sn-1 is occupied by a long chain (C18 or C24) ether-linked alkyl moiety and position sn-2 by a saturated fatty acid (12:0 to 26:0). However, forms with simple fatty acid compositions, such as two myristic acid residues (14:0) are also known. Some GPI anchors contain an additional fatty acid, often 16:0, attached to position 2 of the inositol ring; this has the important property of inhibiting the action of phospholipase C. In mammalian GPIs, the sn-2-linked fatty acid is usually 18:0, while the sn-1-linked chain is C18 or C16, sometimes with one double bond, but there are many exceptions. It is worth noting that phosphatidylinositol per se in animals is very different in that it contains trace amounts only of 1-alkyl,2-acyl forms and the 2-acyl group is predominantly arachidonic acid.
The Man(α1-4)GlcN(α1-6)-myo-inositol-1-HPO4 lipid part is highly conserved (from yeast to humans), indicating that all are part of a single family of complex molecules. Similarly, the core glycan Man(α1-2)Man(α1-6)Man(α1-4)GlcN(α1-6)-myo-inositol is conserved, although it can be substituted in a species-specific manner with side-chains such as ethanolamine phosphate. A distinctive feature in comparison with other complex glycolipids is that the glucosamine residues are only rarely acetylated. As an example, the GPI anchor for acetylcholinesterase from human erythrocytes is illustrated. It has either an 18:0 or an 18:1 alkyl group attached to position sn-1 of the phosphatidylinositol moiety with a 22:4, 22:5 or 22:6 acyl group linked to position sn-2, and a 16:0 fatty acid linked to position 2 of inositol. In type-1 GPIs, there are two ethanolamine phosphate residues attached to the glycan core. In other types, there can be an oligosaccharide side-chain attached to the first mannose, e.g. N-acetylgalactosamine-galactose-sialic acid.
Certain protozoa and trypanosomatid parasites contain type-2 and hybrid GPIs, which differ at one of the hexose linkage points. They also have one fewer ethanolamine phosphate residue than the mammalian form. The phospholipid moiety is variable among protozoan species, and includes diacylglycerol, alkylacylglycerol and ceramide forms, with differing fatty acid constituents. In Leishmania, the GPI-anchor is dominated by phosphoglycosylated glycans, which are related to the lipophosphoglycans and phosphatidylinositol mannosides discussed below.
Free or non-protein-bound glycosyl phosphatidylinositols are present on the external surface of the plasma membrane of some cells both in animals and protozoa (see below), but not in yeasts. Normally, they are present at low levels, but the parasitic protozoan Babesia bovis contains substantial amounts.
Yeasts and plants: Yeasts are distinctive in that they contain both GPI-anchored proteins with a characteristic C26 fatty acid component and ceramide phosphorylinositol(CPI)-anchored proteins; the GPI-anchor is found in both the plasma membrane and cell wall while the CPI-anchor is primarily in the cell wall. With the latter, the ceramide moiety is incorporated by an exchange reaction that occurs after the addition of the GPI precursor to proteins and during transfer to the cell wall with the aid of a protein Cwh43p. Phytosphingosine is the sphingoid base in this instance together with 26:0 fatty acid. Approximately 1% of plant proteins are believed to be GPI-linked, and they are located mainly at the interface of the plasma membrane and cell wall; some have ceramide replacing diacylglycerols as the lipid component as in yeasts. Perhaps surprisingly, these plant molecules are not well characterized as yet, and the glycan core in the only species to have been examined in detail is a relatively simple structure devoid of phosphoethanolamine side chains and with a plant-specific β-linked galactose side chain attached to the first mannose.
2. Biosynthesis and Function of GPI-Protein Complexes
Biosynthesis: Considerable progress has been made towards and understanding of the biosynthesis of GPI-protein complexes, and it is apparent that both the biosynthesis of GPI precursors and post-translational modification of proteins with GPI take place in the endoplasmic reticulum (ER) and Golgi. The process is highly complex and briefly it starts on the cytoplasmic side of endoplasmic reticulum and is completed on the lumenal side, so the intermediate glycophospholipid must be flipped across the membrane.
In mammalian cells, the lipid precursor is a phosphatidylinositol molecule with 1,2-diacyl moieties, which is first attached to an N-acetylglucosamine residue. This is de-acetylated, enabling the molecule to be translocated to the other side of the membrane, presumably by an as yet unidentified flippase. Then, a saturated fatty acid (usually palmitate) is attached to the inositol residue, and the resulting GlcN-(acyl)PI is subjected to a process of lipid remodelling, which converts the diacyl PI moiety to a mixture of 1-alkyl-2-acyl PI, the main form, and disaturated, diacyl-PI, again by enzymes that have still to be characterized, although it should be noted that ether formation usually requires a peroxisomal step. This is followed by a sequence of reactions in which two mannose residues are linked to the glucosamine moiety by dolichol phosphate mannose synthase (also important for the synthesis of glycoproteins - see the web page on dolichol phosphates) before attachment of the first ethanolamine phosphate moiety (derived from phosphatidylethanolamine) to mannose I. After a further mannose unit and then ethanolamine phosphate residues are added to mannose II and III, the protein component can be attached.
In some instances, the first mannose unit is decorated by the addition of a short oligosaccharide sequence, starting with N-acetylgalactosamine. While detailed discussion is best left to carbohydrate experts, an interesting feature is that galactose is then added by the action of a GM1 ganglioside synthase requiring the presence of lactosylceramide, i.e. a link between glycerolipid and sphingolipid metabolism.
The GPI proteins all contain a characteristic carboxyl-terminal signal peptide with a hydrophobic tail, which is split off before the protein with a new carboxyl-terminal is combined with the amino group of the ethanolamine residue on mannose III of the GPI moiety. A GPI-transamidase complex catalyses the overall process of cleavage and GPI attachment. The palmitate attached to inositol and the ethanolamine phosphate on mannose II may then be removed before the GPI-anchored proteins are transported to the Golgi. Here, the unsaturated fatty acid in position sn-2 of the glycerol moiety is removed by the action of phospholipase A2 to form a lyso-GPI-protein, and this is re-acylated with a saturated acid (mainly 18:0 in mammalian cells). In yeast, the lipid remodeling event (addition of 26:0) occurs in the ER and is essential for the efficient transport of GPI-APs from the ER to the Golgi apparatus. Remodelling of the glycan side-chain by removal of an ethanolamine phosphate residue and addition of an N-acetylgalactosamine unit can also occur, for example in yeast when the molecule is transferred from the plasma membrane to the cell wall.
Overall, this remodelling process converts the GPI anchor into a transport signal that actively promotes the sorting and export of GPI-proteins from the endoplasmic reticulum (ER) by a vesicular mechanism to the Golgi apparatus, from where they are transferred to their functional site, the outer leaflet of the plasma membrane. This export system is driven by the cytosolic coat complex COPII, which forms vesicles at ER exit sites for transport of secretory cargo to the Golgi apparatus. GPI-anchored proteins use a specialized form of this machinery for assembly and selective export from the ER, and their processing and maturation may regulate COPII function.
The flexible carbohydrate linkage provides GPI-proteins with a much higher degree of rotational freedom than is available to most other membrane proteins, facilitating their functions as signal receptors and host-recognition molecules. They have essential functions in the interaction of cells with their external environment by enabling the receipt of signals and the response to challenges as well as mediating adhesion of extracellular compounds to the cell surface.
Function: GPI-anchored proteins have a diverse range of functions, but many are hydrolytic enzymes (including peptidases) or serve as receptors, cell surface antigens or cell adhesion molecules. Most of them can be identified from proteomic analysis or DNA analysis of the appropriate genes by the presence of the characteristic N- and C-terminal signal peptides. While its complexity suggests that a variety of functions might be possible, it seems that the main purpose of the GPI anchor is to act as a stable anchoring device that resists the action of most extracellular proteases and lipases. It targets its protein/enzyme component to a particular membrane, where it is required for its specific function. However, some further movement is possible and transfer between membranes and even between cells can take place. As an example, high-density lipoprotein-binding protein 1 (GPIHBP1) is a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells; this picks up the enzyme lipoprotein lipase, a key enzyme in plasma triacylglycerol metabolism, from the interstitial spaces and transports it across endothelial cells to the capillary lumen where it can function.
In addition, the nature of the hydrophobic moiety with its saturated fatty acid components, resembling that of a ceramide, ensures that the GPI anchor is readily incorporated into those regions of the apical plasma membrane enriched in sphingolipids and cholesterol and termed ‘rafts’, where the glycan core may aid lateral mobility. Both saturated acyl/alkyl moieties in the GPI anchor are essential for raft association to occur, but the anchored proteins may also affect microdomain formation by forming transient homodimers. There also seems to be a need for an interaction with phosphatidylserine in the inner leaflet of the plasma membrane and with the underlying actin cytoskeleton. In animals, GPI-anchored proteins are essential for the fertility of mouse sperm and egg, and for coordinated growth during embryonic development. They can act as signalling molecules to mediate cell–cell communication. For example, the GPI-anchor may function as a sorting signal for transport of GPI-anchored proteins in the secretory and endocytic pathways, facilitated by the remodelling processes that occur in the Golgi.
In the brain, GPI-anchored proteins perform diverse functions in the dynamic control of axon and synapse function and local signal transduction within raft domains. In particular, they are key synapse organizers that help to determine the properties of various types of synapses and circuits. GPI-anchored glycoproteins of the immunoglobulin superfamily mediate interactions between neurons and also between neurons and other cells in the nervous system and so play a part in the regulation of neuronal development, synapse formation, and many other brain functions.
Release of GPI-anchored proteins: GPI-linked proteins are not as tightly anchored to the membrane as transmembrane proteins and so can migrate from one cell to another enabling cell communication. Thus, GPI proteins attached to their GPI anchors are released from the plasma membrane into the intercellular medium, sometimes via membrane vesicles, and they are found in serum and other body fluids. These can be re-inserted spontaneously into cell membranes and so participate in cell–cell interactions enabling control over the behaviours of neighboring cells.
Alternatively, the lipid anchor can be removed through the activity of phospholipases, such as phosphatidylinositol-specific phospholipases C and D, by a process termed ‘shedding’, which frees particular proteins selectively, perhaps as part of a regulatory mechanism. A mammalian GPI-specific phospholipase D, GPLD1, which is a soluble protein abundant in serum, hydrolyses a specific set of GPI anchors that have acylated inositol, in contrast to those GPI anchors cleaved by phosphatidylinositol-phospholipase C and GPI-phospholipase C. PGAP6, a GPI-specific phospholipase A2, has narrow substrate specificity towards certain GPI-anchored proteins involved in embryonic development; it removes one of the fatty acids and so releases the proteins from the membranes.
Free (unlinked) glycosylphosphatidylinositols have also been detected on the surfaces of several mammalian cell types in studies with monoclonal antibodies, and they may be normal membrane components in some tissues at least. These are not hydrolysis products but are formed in the same way as the GPI-anchored forms at the endoplasmic reticulum and transported as such to the plasma membrane. In this process, they undergo fatty acid remodelling, inositol deacylation, removal of the ethanolamine phosphate from the second mannose,. and modification with N-acetylgalactosamine side-chains with or without elongation by galactose.
GPI-anchored proteins and health: There is little doubt that GPI anchoring is essential for mammalian embryogenesis, development, neurogenesis, fertility and the immune system. When defects occur at any stage in the biosynthetic process, there are serious metabolic consequences and a number of human genetic disorders due to faulty GPI synthesis are known; animals with major defects in the biosynthesis of GPI anchors do not survive beyond the embryo stage. They stimulate the immune system in mammalian host tissues by activating macrophages and promoting the release of different proinflammatory cytokines and chemokines, such as tumor necrosis factor-alpha, interleukin-1 and nitric oxide. Defects in the regulatory mechanisms involving GPI-anchored proteins may underlie various brain disorders and cancer.
GPI-anchored proteins are involved in a number of other diseases, and for example, when associated with lipid rafts, they can be incorporated into the lipid envelopes of viruses, where they may promote viral replication. In T. brucei and related species, GPI-anchor proteins, especially a glycoprotein termed the ‘promastigote surface protease’, accompanied by lipophosphoglycans (see below) form a dense layer or glycocalyx as a protective barrier around the organism. This protects against the host defense systems, and it has also been implicated in "hijacking" proteins involved in host innate immunity. A further important example is the prion protein responsible for ‘mad cow’ disease where the GPI-anchor may have a role in the pathogenicity of the disease. Similarly, certain bacterial toxins bind to GPI-anchors to exert their pathological effects. Synthetic GPIs are under investigation for many biomedical applications, for example as potential vaccines against such intractable parasitic diseases as malaria.
Other eukaryotic species: While the synthesis and structure of GPI-anchored proteins are well conserved within eukaryotes, there are striking diversities in their cellular functions, and some variations are built into the biosynthetic pathway. For example, in many protozoan parasites, they are the major form of cell surface proteins, which protect the cell from the defenses of their hosts. In yeast and fungi, GPI-anchored proteins participate in the structural integrity of the cell wall through covalent linkages to polysaccharides, and so are essential for the viability and survival of the organisms. Thus, the developing GPI-anchored proteins tend to be heavily glycosylated by both N- and O-glycosylations in the endoplasmic reticulum and Golgi during their transit to the plasma membrane and thence to the cell wall, where they form further glycosidic linkages with other mannoproteins. The result is that a complex mannoprotein lattice is presented to the external environment. In addition, the lipid moieties of mature GPI-anchors of yeast contain a modified diacylglycerol with a 26:0 fatty acid in position sn-2, that is introduced in the Golgi apparatus and not in the endoplasmic reticulum.
In plants, GPI-anchored proteins affect a number of biological processes at the interface of the plasma membrane and cell wall, and these include cell wall metabolism, cell wall polymer cross-linking, plasmodesmatal transport, and the response to plant pathogens. They have the potential to transfer signals into the protoplast and thus activate signalling pathways. In particular, they are believed to be essential for many aspects of sexual plant reproduction, for example in the fertility of the male and female gametophytes and in the interactions between pollen/pollen tube and pistil tissues during pollination.
3. Lipophosphoglycans and Phosphatidylinositol Mannosides
Lipophosphoglycans: In addition to the GPI-anchor molecules, carbohydrates attached to phosphatidylinositols play a role in the surface antigenicity both of certain protozoal parasites, such as the Trypanosomatid family, and of prokaryotic organisms, such as Actinomycetes or coryneform bacteria. In particular in the parasitic protozoal parasites, lipophosphoglycans are present in a glycocalyx that covers the external cell surface, where they are intimately involved in host-pathogen interactions. The lipophosphoglycans of Leishmania species, the causative agent of leishmaniases and an intracellular parasite of macrophages transmitted to humans via the bite of its sand fly vector, have received intensive study. However, all of the surface-bound molecules of the Trypanosomatid family have a common structural feature in that they contain a highly conserved GPI-anchor motif that differs significantly from those in mammalian cells.
In most trypanosomatids, the glycocalyx is composed mainly of GPI-anchored glycoproteins, but in that of the Leishmania promastigote stage GPI-anchored phosphoglycosylated glycans predominate. They are based on a type-2 GPI core, Manα1-3Manα1-4GlcNα1-6PI, as part of a conserved hexaglycosyl unit, which is attached to a long phosphodisaccharide-repeat domain (15 to 40 units) that carries species-specific side-chain modifications and is completed by a neutral oligosaccharide consisting of 2, 3 or 4 galactose and mannose units. The lipid component is a monoalkyl-lysophosphatidylinositol with saturated C24 to C26 alkyl groups. These lipophosphoglycans are essential for successful invasion of the host animal. In addition, the galactofuranose unit (Galf), which does not occur in mammalian cells, is believed to play a part in the pathogenicity.
Low-molecular-weight (free) glycosylinositol phospholipids occur in the organisms also with a glycan core that is similar structurally to that of the glycan core of the lipophosphoglycan or to that of the GPI-anchored glycoprotein. The protozoan parasite Toxoplasma gondii expresses non-protein-linked GPI, which are highly immunogenic. Analogous lipophosphoglycans with the lipid backbone consisting of a ceramide, i.e. ceramide phosphorylinositol, rather than a diacylglycerol, are also found in nature, especially in plants, yeasts and other fungi.
Phosphatidylinositol mannosides: These are related lipids with the first mannose residue attached to the 2-hydroxyl group and the second to the 6-hydroxyl of myo-inositol that are found uniquely in the cell walls of the bacterial suborder Corynebacterineae, which include Mycobacteria and related species, many of which are important pathogens. In Mycobacteria sp., phosphatidylinositol and phosphatidylinositol mannosides amount to 56% of all phospholipids in the cell wall and 37% in the cytoplasmic membrane. Phosphatidylinositol mannosides range in structure from simple mono-mannosides in some Streptomyces and Mycobacterium species and in Propionibacteria to molecules with 80 or more hexose units. They are important structural components of membranes with functions in cell wall integrity, permeability and division.
The phosphatidylinositol dimannoside from M. tuberculosis, M. phlei and M. smegmatis illustrated has been characterized as 1-phosphatidyl-L-myo-inositol 2,6-di-O-α-D-mannopyranoside. This is the basic structure from which additional phosphatidylinositol mannosides are produced, and with two further acylations (designated Ac2PIM2) it is the major lipid component of the inner leaflet of the inner membrane. Similarly, forms with up to four further mannose units are present, and a hexamannoside (Ac2PIM6) especially on the outer leaflet of the inner membrane is often a major component. The main fatty acid constituents are palmitic and 10-methyl-stearic (tuberculostearic) acids, and they can have one to four fatty acyl groups in total, with the additional fatty acyl substituents linked to position 2 of the inositol moiety and/or position 6 of one of the inner mannose units. Phosphatidylinositol mannosides can be grouped into lower- and higher-order species depending on their number of mannoses, one to four mannoses in the former and five to six mannoses in the latter. All lower-order species have a terminal α1,6-mannose, while higher order have a terminal α1,2-mannose.
Biosynthesis of such complex lipids involves a number of reactions, and it is apparent that the first two mannosylation steps of the pathway occur on the cytoplasmic face of the plasma membrane by the action of two distinct phosphatidylinositol mannosyltransferases, which are essential for the viability of the organism and are seen as potential drug targets. The additional acylations also occur on this membrane, probably after synthesis of the dimannoside. On the other hand, further mannosylations require first a transfer to the periplasmic side of the membrane and then the action of integral membrane-bound glycosyltransferases, but many of these enzymes have yet to be identified. It is evident that these lipids modulate the inflammatory and immune system responses in host animals in many different ways, especially in tuberculosis and leprosy. The web page on mycolic acids contains a more extensive discussion of the cell wall structure and composition of M. tuberculosis, with links to web pages on many other unique lipids from this organism.
Lipomannans from Mycobacteria sp. have a longer chain of mannose units, comprising a backbone of an α1,6-mannose residue attached to phosphatidylinositol, and there can be up to two additional fatty acid components attached to position 6 of the Manp unit and position 3 of the myo-inositol. A α1,2-mannose side chain (mannan) is attached to the inositol unit, and finally an arabinan (arabinose polysaccharide) branch is attached to the mannan to produce the highly complex lipoarabinomannans. For example, in M. tuberculosis, the arabinan component contains a linear polymer of ~70 residues of D-arabinofuranose in α1,5-linkage, modified with α1,3-branch points. The phosphatidylinositol tetramannosides Ac1PIM4 and Ac2PIM4 appear to be the intermediates at the branch point in the biosynthesis of the phosphatidylinositol hexamannosides and of lipomannans and lipoarabinomannans. Such molecules are believed be important for the structural integrity of the cell walls of the organisms, a function similar to that of the lipoteichoic acids.
They have been implicated in host–pathogen interactions in tuberculosis and leprosy. In infected animals, these lipopolysaccharides interact with different receptors and exert potent anti-inflammatory effects, which may assist in repressing the host innate immune system. In particular, lipoarabinomannan binding to lactosylceramide in lipid rafts is essential for the phagocytosis of mycobacteria by human neutrophils. It is hoped that knowledge of the biosynthetic enzymes may lead to improved drug therapies.
Related Lipids: Bacteria of the genus Thermomicrobia contain unusual long-chain 1,2-diol-containing phosphoinositides and inositolmannosides in which the stereochemistry of the diol unit is the same as the corresponding positions in sn-glycerol-3-phosphate. C17 to C23 Straight-and branched-chain saturated fatty acids are linked to position 2 of the diol.
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