Glycophosphatidylinositol
Encyclopedia
Glycosylphosphatidylinositol (GPI anchor) is a glycolipid
that can be attached to the C-terminus of a protein
during posttranslational modification
. It is composed of a phosphatidylinositol
group linked through a carbohydrate
-containing linker (glucosamine
and mannose
glycosidically bound to the inositol
residue) and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The two fatty acids within the hydrophobic phosphatidyl-inositol group anchor the protein to the cell membrane
.
Glypiated (GPI-linked) proteins contain a signal peptide
, thus directing them into the endoplasmic reticulum
(ER). The C-terminus is composed of hydrophobic amino acids that stay inserted in the ER membrane. The hydrophobic end is then cleaved off and replaced by the GPI-anchor. As the protein processes through the secretory pathway
, it is transferred via vesicles to the Golgi apparatus
and finally to the extracellular space where it remains attached to the exterior leaflet of the cell membrane
. Since the glypiation is the sole means of attachment of such proteins to the membrane, cleavage of the group by phospholipases will result in controlled release of the protein from the membrane. The latter mechanism is used in vitro
; i.e., the membrane proteins released from the membranes in the enzymatic assay are glypiated protein.
Phospholipase C
(PLC) is an enzyme that is 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 marker Thy-1 and acetylcholinesterase
, 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
s, suggesting a high level of organization within plasma membrane microdomains.
(PNH) and hyperphosphatasia with mental retardation syndrome
(HPMR). In PNH a clonal defect in blood stem cells in the gene PIGA
, that is required for GPI synthesis, results in faulty GPI linkage of decay-accelerating factor (DAF) and CD59
in red blood cell
s. Without these proteins linked to the cell surface, the complement system
can lyse the cell, and high numbers of RBCs are destroyed, leading to hemoglobinuria
.
Glycolipid
Glycolipids are lipids with a carbohydrate attached. Their role is to provide energy and also serve as markers for cellular recognition.-Metabolism:...
that can be attached to the C-terminus of a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
during posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
. It is composed of a phosphatidylinositol
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
group linked through a carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
-containing linker (glucosamine
Glucosamine
Glucosamine is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. Glucosamine is part of the structure of the polysaccharides chitosan and chitin, which compose the exoskeletons of crustaceans and other arthropods, cell walls in fungi and...
and mannose
Mannose
Mannose is a sugar monomer of the aldohexose series of carbohydrates. Mannose is a C-2 epimer of glucose. It is not part of human metabolism, but is a component of microbial cell walls, and is therefore a target of the immune system and also of antibiotics....
glycosidically bound to the inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
residue) and via an ethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The two fatty acids within the hydrophobic phosphatidyl-inositol group anchor the protein to the cell membrane
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
.
Glypiated (GPI-linked) proteins contain a signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
, thus directing them into the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER). The C-terminus is composed of hydrophobic amino acids that stay inserted in the ER membrane. The hydrophobic end is then cleaved off and replaced by the GPI-anchor. As the protein processes through the secretory pathway
Secretory pathway
The secretory pathway is a series of steps a cell uses to move proteins out of the cell; a process known as secretion. The path of a protein destined for secretion has its origins in the rough endoplasmic reticulum, a membrane-bound compartment in the cell...
, it is transferred via vesicles to the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
and finally to the extracellular space where it remains attached to the exterior leaflet of the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. Since the glypiation is the sole means of attachment of such proteins to the membrane, cleavage of the group by phospholipases will result in controlled release of the protein from the membrane. The latter mechanism is used in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
; i.e., the membrane proteins released from the membranes in the enzymatic assay are glypiated protein.
Phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) is an enzyme that is 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 marker Thy-1 and acetylcholinesterase
Acetylcholinesterase
"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...
, 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
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
s, suggesting a high level of organization within plasma membrane microdomains.
GPI-anchor synthesis deficiencies
Defects in the GPI anchors synthesis occur in the rare diseases paroxysmal nocturnal hemoglobinuriaParoxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...
(PNH) and hyperphosphatasia with mental retardation syndrome
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...
(HPMR). In PNH a clonal defect in blood stem cells in the gene PIGA
PIGA
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is an enzyme that in humans is encoded by the PIGA gene.-Further reading:...
, that is required for GPI synthesis, results in faulty GPI linkage of decay-accelerating factor (DAF) and CD59
CD59
Protectin, a complement regulatory protein, also known as ', or MIRL is a human gene and protein....
in red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s. Without these proteins linked to the cell surface, the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
can lyse the cell, and high numbers of RBCs are destroyed, leading to hemoglobinuria
Hemoglobinuria
In medicine, hemoglobinuria or haemoglobinuria is a condition in which the oxygen transport protein hemoglobin is found in abnormally high concentrations in the urine. The condition is often associated with hemolytic anemia, in which red blood cells are destroyed, thereby increasing levels of free...
.
External links
- http://upload.wikimedia.org/wikibooks/en/thumb/7/7c/GPI-Anchor.jpg/180px-GPI-Anchor.jpg