| GPI synthesis components | |
|---|---|
| Identifiers | |
| Symbol | GPI |
| Membranome | 327 |
Glycosylphosphatidylinositol (pronunciationⓘ) orglycophosphatidylinositol (GPI) is aphosphoglyceride that can be attached to theC-terminus of aprotein duringposttranslational modification. The resultingGPI-anchored proteins play key roles in a wide variety of biological processes.[1] GPI is composed of aphosphatidylinositol group linked through acarbohydrate-containing linker (glucosamine andmannose glycosidically bound to theinositol residue) and via anethanolamine phosphate (EtNP) bridge to the C-terminal amino acid of a mature protein. The twofatty acids within the hydrophobic phosphatidyl-inositol group anchor the protein to thecell membrane.
Glycosylated (GPI-anchored) proteins contain asignal sequence, thus directing them to theendoplasmic reticulum (ER). The protein is co-translationally inserted in the ER membrane via atranslocon 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 thesecretory pathway, it is transferred via vesicles to theGolgi apparatus and finally to the plasma membrane where it remains attached to a leaflet of thecell membrane. Since theglypiation is the sole means of attachment of such proteins to the membrane, cleavage of the group byphospholipases will result in controlled release of the protein from the membrane. The latter mechanism is usedin vitro; i.e. membrane proteins released from membranes in enzymatic assays are glypiated proteins.[citation needed]
The inositol residue is modified withpalmitate ormyristate at position 2 prior to mannose and ethanolamine phosphate transfer.[2] 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, inerythrocytes, the majority of GPI-anchored proteins are acylated with myristate on the anchor.[3] InTrypanosoma brucei, by contrast, mannosyltransferase activity does not require acylation of the inositol residue[4] and consequently unacylated GPI anchors are transferred to the parasite'svariant surface glycoprotein.[3]
Phospholipase C (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.[3] TheT-cell marker Thy-1 andacetylcholinesterase, as well as bothintestinal andplacental alkaline phosphatases, are known to be GPI-linked and are released by treatment with PLC. GPI-linked proteins are thought to be preferentially located inlipid rafts, suggesting a high level of organization within plasma membrane microdomains.[citation needed]
Defects in the GPI-anchor synthesis occur in rare acquired diseases such asparoxysmal nocturnal hemoglobinuria (PNH) and congenital diseases such ashyperphosphatasia 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 ofdecay-accelerating factor (DAF) andCD59 inred blood cells. The most common cause of PNH are somatic mutations in the X-chromosomal genePIGA. However, a PNH case with agermline mutation in the autosomal genePIGT and a second acquired somatic hit has also been reported.[5]Without these proteins linked to the cell surface, thecomplement system canlyse the cell, and high numbers of RBCs are destroyed, leading tohemoglobinuria.For patients with HPMRS, disease-causing mutations have been reported in the genesPIGV,PIGO,PGAP2 andPGAP3.[citation needed]
Thevariable surface glycoproteins from thesleeping sickness protozoanTrypanosoma brucei are attached to the plasma membrane via a GPI anchor.[6]
