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Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a
phosphoglyceride Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes. Two major classes are known: those for bacteria and eukaryotes and a separate family for archaea. Structures The t ...
that can be attached to the
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...
of a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
during
posttranslational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...
. The resulting
GPI-anchored protein Lipid-anchored proteins (also known as lipid-linked proteins) are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilay ...
s play key roles in a wide variety of biological processes. GPI is composed of a
phosphatidylinositol Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
group linked through a
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...
-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 most ...
and
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
glycosidically bound to the
inositol Inositol, or more precisely ''myo''-inositol, is a carbocyclic sugar that is abundant in the brain and other mammalian tissues; it mediates cell signal transduction in response to a variety of hormones, neurotransmitters, and growth factors and ...
residue) and via an
ethanolamine phosphate Phosphorylethanolamine or phosphoethanolamine is an ethanolamine derivative that is used to construct two different categories of phospholipids. One category termed a glycerophospholipid and the other a sphingomyelin, or more specifically within th ...
(EtNP) bridge to the C-terminal amino acid of a mature protein. The two
fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
within the hydrophobic phosphatidyl-inositol group anchor the protein to the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
.


Synthesis

Glycosylated (GPI-anchored) proteins contain a signal sequence, thus directing them to the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
(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 transport ...
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 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classica ...
, 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 cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
and finally to the plasma membrane where it remains attached to a leaflet of the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. Since the
glypiation Glypiation is the addition by covalent bonding of a glycosylphosphatidylinositol (GPI) anchor and is a common post-translational modification that localizes proteins to cell membranes. This special kind of glycosylation is widely detected on surfac ...
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. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
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'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
''; i.e. membrane proteins released from membranes in enzymatic assays are glypiated proteins.


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 ...
(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. The
T-cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells 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 r ...
marker Thy-1 and
acetylcholinesterase Acetylcholinesterase ( 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 that catalyzes the breakdown of ac ...
, as well as both intestinal and
placental alkaline phosphatase Alkaline phosphatase, placental type also known as placental alkaline phosphatase (PLAP) is an allosteric enzyme that in humans is encoded by the ''ALPP'' gene. Gene There are at least four distinct but related alkaline phosphatases: intestina ...
s, 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 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 ...
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 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occu ...
(PNH) and congenital diseases such as
hyperphosphatasia with mental retardation syndrome Hyperphosphatasia with mental retardation syndrome, HPMRS, also known as Mabry syndrome, has been described in patients recruited on four continents world-wide. Mabry syndrome was confirmed to represent an autosomal recessive syndrome characterized ...
(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 surface. It recognizes C4b and C3b fragments that are created during ...
(DAF) and CD59 in
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s. The most common cause of PNH are somatic mutations in the X-chromosomal gene PIGA. However, a PNH case with a germline mutation in the autosomal gene
PIGT GPI transamidase component PIG-T is an enzyme that in humans is encoded by the ''PIGT'' gene. This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid found on many bl ...
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 immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
can lyse the cell, and high numbers of RBCs are destroyed, leading to
hemoglobinuria Hemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is caused by excessive intravascular hemolysis, in which large numbers of red blood cells (RBCs) ...
. For patients with HPMRS, disease-causing mutations have been reported in the genes ''
PIGV GPI mannosyltransferase 2 is an enzyme that in humans is encoded by the ''PIGV'' gene. See also *Hyperphosphatasia with mental retardation syndrome Hyperphosphatasia with mental retardation syndrome, HPMRS, also known as Mabry syndrome, has been ...
'', ''
PIGO The pigoKottelat, M. and J. Freyhof, 2007. Handbook of European freshwater fishes. Publications Kottelat, Cornol, Switzerland. 646 p. (''Rutilus pigus'') is a species of freshwater fish in the roach genus ''Rutilus'' of the family Cyprinidae. The ...
'', ''
PGAP2 1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cy ...
'' and '' PGAP3''.


In other species

The
variable surface glycoprotein Variant surface glycoprotein (VSG) is a ~60kDa protein which densely packs the cell surface of protozoan parasites belonging to the genus ''Trypanosoma''. This genus is notable for their cell surface proteins. They were first isolated from ''Tryp ...
s from the sleeping sickness protozoan ''
Trypanosoma brucei ''Trypanosoma brucei'' is a species of parasitic 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 exclusively extrace ...
'' are attached to the plasma membrane via a GPI anchor.


References


External links

* * {{Phospholipids Membrane biology Post-translational modification