GPI-anchored protein

GPI anchoring is a posttranslational modification occurring in the endoplasmic reticulum where preassembled GPI anchor precursors are transferred to proteins bearing a C-terminal GPI signal sequence. The GPI anchor precursors are synthesized in the endoplasmic reticulum by sequential addition of sugar and other components to phosphatidylinositol. Protein GPI anchors are ubiquitous in eukaryotic cells. In mammalian cells, GPI anchored proteins are often found in lipid rafts which are subdomains of the plasma membrane, containing various signaling components. 

GPI-anchored proteins constitute a quite diverse family of cell-surface molecules that participate in such processes as nutrient uptake, cell adhesion, and membrane signaling events [3]. All GPI-linked proteins are destined for the cell surface via trafficking through the secretory pathway, where they acquire the... 

Paroxysmal nocturnal hemoglobinemia (MIM 311770) Mutations in the PIG-A gene, affecting synthesis of GPI-anchored proteins... 

Kenworthy, A. K., Petranova, N. and Edidin, M. (2000). High resolution FRET microscopy of cholera toxin B-subunit and GPI-anchored proteins in cell plasma membranes. Mol. Biol. Cell 11, 1645-55. 

Friedrichson, T., and Kurzchalia, T.V. (1998) Microdomains of GPI-anchored proteins in living cells revealed by crosslinking. Nature 394(6695), 802-805. 

Much of the plasma membrane cholesterol is removed by incubating cells with P-methylcyclodextrin for several hours. Cells remain viable after this treatment but the raft fraction is reduced and it is inferred that the depleted proteins are normally associated with cholesterol-dependent lipid rafts. Some, but not all, glycosylphosphatidylinositol (GPI)-anchored proteins are recovered in the fractions defined by this procedure. 

GPI-anchored proteins (GP-APs) are synthesized in the cytoplasm and their transport into the ER occurs during the process of acquiring a GPI anchor, which is ultimately sorted into the outer leaflet of plasma membranes [24], A FRET study of fluorophore-labeled GPI-APs in cultured... 

Sharma, P., Varma, R., Sarasij, R. C., Gousset, K., Krishnamoorthy, G. and Rao M, Mayor S. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 116 577-589, 2004. 

Medof, M. E., Nagargian, S. and Tykocinski, M. L. Cell-surface engineering with GPI-anchored proteins. FASEB J. 10 574-586,1996. 

Members of this family of molecules may have only one Ig-like domain, as is the case for the myelin protein P0, or, as for most of the family, have many Ig domains. In addition to the subclassification of Ig domains into V-, C- and C2-like domains, Ig family members can be broadly divided into three general classes [8] (a) those that have only Ig-like domains (b) those that have Ig domains and additional domains that resemble regions of the ECM component fibronectin, termed FN-like domains and (c) those that have Ig domains and motifs other than FN-like domains. Moreover, any one Ig family member may have many isoforms, which may differ in the length of the cytoplasmic domain, in their post-translational modifications and whether they are membrane-spanning or glycosylphos-phatidylinositol (GPI)-anchored proteins (see Box 3-1). Also, additional amino acid sequences inserted in the extracellular domain may distinguish isoforms of a particular IgCAM. While it is not known how the majority... 

Other pinocytotic pathways also exist that do not depend on either caveolae or clathrin, although these are not as well defined [55]. Specific receptors continue to be internalized in the absence of clathrin or caveolin and these pathways can be monitored by following glycosyl phos-phatidylinositol (GPI (-anchored proteins. Nonclathrin, noncaveolin pathways may also be responsible for the reuptake of membrane in neuroendocrine cells after stimulated secretion. Some, but not all, of these pathways appear to require dynamin. 

The last class of three major membrane anchors is caused by the modification by a glycophospholipid, glycosylphosphatidylinositol (GPI) (Udenfriend and Kodukula, 1995a Takeda and Kinoshita, 1995). They are observed in many eukaryotes, especially in protozoa and yeasts. Unlike other classes, the GPI-anchored proteins are exposed at the (extracytoplasmic) surface of the plasma membrane. Thus, we can predict the localization at the plasma membrane from the presence of a GPI anchor, although some of them are further incorporated into the cell wall in S. cerevisiae (as described in Section III,K,1). 

The GPI-anchored proteins are related to various cellular functions. For example, they participate in the protein sorting to the apical surface of polarized cells and clathrin-independent endocytosis (see Section III,... 

The cell wall of S. cerevisiae is composed of glucan, mannoproteins, and chitin (Klis, 1994 Cid et al., 1995). Of the mannoproteins, some of them are first synthesized as GPI-anchored and mannosylated proteins. Subsequently, they are incorporated from the plasma membrane to the cell wall and are covalently linked to the glucan there. Therefore, some signals should exist for dictating the cell wall incorporation. One found at a short N-terminal region near the GPI-attached asparagine (the co-site) is important (Hamada et al., 1998b). Namely, a plasma membrane GPI-anchored protein was localized to the cell wall if the (V/I)... 

Eisenhaber, B., Bork, P., and Eisenhaber, F. (1998). Sequence properties of GPI-anchored proteins near the co-site constraints for the polypeptide binding site of the putative transamidase. Protein Eng. 11, 1155-1161. 

S. Mayor, K. G. Rothberg, and F. R. Maxfield. Sequestration of GPI-anchored proteins in caveolae triggered by cross-linking. Science 264 1948-1951 (1994). 

J. Wang, W. Gunning, K. M. Kelley, and M. Ratnam. Evidence for segregation of heterologous GPI-anchored proteins into separate lipid rafts within the plasma membrane. J. Membr. Biol. 189 35—43 (2002). 

Molecular targets have been elucidated for Dm-AMPl and Rs-AFP2. Dm-AMPl was found to bind plasma membranes from Neurospora crassa and Saccharomyces cerevisiae in a saturable manner and it competed with closely related defensins for binding. Mutational studies with S. cerevisiae identified lipid raffs containing sphingolipids as a molecular target " while glycosylphosphatidylinositol (GPI)-anchored proteins could be... 

Post-Translational Lipidation of Extracellularly Oriented Proteins 5.17.1.2.1 GPI-Anchored proteins... 

Specific proteins can be covalently attached via a carbohydrate bridge to membrane-bound PI (glycosylphosphatidylinositol, or GPI). This allows GPI-anchored proteins rapid lateral mobility on the surface of the plasma membrane. A deficiency in the synthesis of GPI in hematopoietic cells results in a hemolytic disease, paroxysmal nocturnal hemoglobinuria. 

T. Kinoshita Enzymes required for biosynthesis of GPI-anchored proteins H. Kunz Synthetic glycopeptides for the development of antitumor vaccines M. A. J. Ferguson GPI and glycoprotein biosynthesis as targets for anti-parasite design... 

Morbiato L, Carli L, Johnson E, Montecucco C, Molgo J et al. (2007) Neuromuscular paralysis and recovery in mice injected with botulinum toxin A and C Eur J Neurosci 25 2697-704 Munro P, Kojima H, Dupont JL, Bossu JL, Poulain B et al. (2001) High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein. Biochem Biophys Res Commun 289 623-9... 

Mayor, S., Sabharanjak, S., and Maxfield, F. R. (1998). Cholesterol-dependent retention of GPI-anchored proteins in endosomes. EMBO J. 17(16), 4626-4638. 

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