Glycosylphosphatidylinositol () or glycophosphatidylinositol (GPI) is a phosphoglyceride that can be attached to the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

of a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

during

posttranslational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA ...

. The resulting GPI-anchored proteins play key roles in a wide variety of biological processes. GPI is composed of a

phosphatidylinositol Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found ...

group linked through a

carbohydrate A carbohydrate () is a biomolecule composed of carbon (C), hydrogen (H), and oxygen (O) atoms. The typical hydrogen-to-oxygen atomic ratio is 2:1, analogous to that of water, and is represented by the empirical formula (where ''m'' and ''n'' ...

-containing linker (

glucosamine Glucosamine (C6H13NO5) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of two polysaccharides, chitosan and chitin. Glucosamine is one of the mo ...

and

mannose Mannose is a sugar with the formula , which sometimes is abbreviated Man. It is one of the monomers of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylatio ...

glycosidically bound to the

inositol In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its elemental formula, formula is ...

residue) and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The two

fatty acids In chemistry, in particular 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, ...

within the hydrophobic phosphatidyl-inositol group anchor the protein to the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

Synthesis

Glycosylated (GPI-anchored) proteins contain a signal sequence, thus directing them to the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(ER). The protein is co-translationally inserted in the ER membrane via a

translocon The translocon (also known as a translocator or translocation channel) is a complex of proteins associated with the translocation of polypeptides across membranes. In eukaryotes the term translocon most commonly refers to the complex that transpor ...

and is attached to the ER membrane by its hydrophobic C terminus; the majority of the protein extends into the ER lumen. The hydrophobic C-terminal sequence is then cleaved off and replaced by the GPI-anchor. As the protein processes through the

secretory pathway Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell (biology), cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. Th ...

, it is transferred via vesicles to the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

and finally to the plasma membrane where it remains attached to a leaflet of the

. Since the glypiation is the sole means of attachment of such proteins to the membrane, cleavage of the group by

phospholipase A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C, and D, which are distinguished by the type of reaction which they catalyze: *Phospholipase ...

s will result in controlled release of the protein from the membrane. The latter mechanism is used ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''; i.e. membrane proteins released from membranes in enzymatic assays are glypiated proteins. The inositol residue is modified with palmitate or myristate at position 2 prior to mannose and ethanolamine phosphate transfer. This is most often removed soon after addition to the C terminus of a protein in the endoplasmic reticulum; in nucleated cells, only 5 to 10 percent of mature GPI-anchored proteins retain the marker, however, in

erythrocyte Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood ce ...

s, the majority of GPI-anchored proteins are acylated with myristate on the anchor. In ''

Trypanosoma brucei ''Trypanosoma brucei'' is a species of parasitic Kinetoplastida, kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is excl ...

'', by contrast, mannosyltransferase activity does not require acylation of the inositol residue and consequently unacylated GPI anchors are transferred to the parasite's variant surface glycoprotein.

Cleavage

Phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...

(PLC) is an enzyme known to cleave the phospho-glycerol bond found in GPI-anchored proteins. Treatment with PLC will cause release of GPI-linked proteins from the outer cell membrane, but acylation of the inositol residue can interfere with PLC cleavage. The

T-cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their ce ...

marker Thy-1 and

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

, as well as both intestinal and placental alkaline phosphatases, are known to be GPI-linked and are released by treatment with PLC. GPI-linked proteins are thought to be preferentially located in

lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organized in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular me ...

s, suggesting a high level of organization within plasma membrane microdomains.

GPI-anchor synthesis deficiencies

In humans

Defects in the GPI-anchor synthesis occur in rare acquired diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and congenital diseases such as hyperphosphatasia with mental retardation syndrome (HPMRS). In PNH a somatic defect in blood stem cells, which is required for GPI synthesis, results in faulty GPI linkage of

decay-accelerating factor Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the ''CD55'' gene. DAF regulates the complement system on the Cell (biology), cell surface. It recognizes C4b and C3b fragments that are ...

(DAF) and CD59 in

red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

s. The most common cause of PNH are somatic mutations in the X-chromosomal gene '' PIGA''. However, a PNH case with a

germline mutation A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and Egg cell, ova). Mutations in these cells are the only mutations that can be passed on to offspring, when e ...

in the autosomal gene '' PIGT'' and a second acquired somatic hit has also been reported. Without these proteins linked to the cell surface, the

complement system The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...

can lyse the cell, and high numbers of RBCs are destroyed, leading to hemoglobinuria. For patients with HPMRS, disease-causing mutations have been reported in the genes '' PIGV'', '' PIGO'', '' PGAP2'' and '' PGAP3''.

In other species

The variable surface glycoproteins from the

sleeping sickness African trypanosomiasis is an insect-borne parasitic infection of humans and other animals. Human African trypanosomiasis (HAT), also known as African sleeping sickness or simply sleeping sickness, is caused by the species '' Trypanosoma b ...

protozoan ''

'' are attached to the plasma membrane via a GPI anchor.

References

External links

* * {{Phospholipids Membrane biology Post-translational modification