ReviewStructural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins
Highlights
► We review recent progress in studies on glycosylphosphatidylinositol (GPI). ► Three different GPI remodeling reactions occur in GPI-anchored proteins during the transport to the cell surface. ► GPI is an important factor that defines the behaviors of GPI-anchored proteins, such as trafficking and signal transductions. ► Several inherited and acquired diseases such as paroxysmal nocturnal hemoglobinuria are caused by impaired GPI biosynthesis. ► GPI is implicated in pathogenesis of the prion disease.
Introduction
The presence of proteins anchored to the plasma membrane via phosphatidylinositol (PI) was first indicated in the 1970’s, because particular proteins were released from the surface following treatment with phosphatidylinositol-specific phospholipase C [1], [2], [3], [4], [5]. In the mid-1980’s compositional and structural data on Torpedo [6], human acetylcholinesterases [7], rat Thy-1 [8] and Trypanosoma brucei VSG [9], [10] reported the presence of GPI-anchors for these proteins. The complete GPI-anchor structures in T. brucei of VSG [11] and rat Thy-1 [12] were reported in 1988. Thus, the concept of the GPI was established. In the same period, several interesting findings on the biological significance of GPI-APs, such as signaling, protein trafficking and the accumulation in specialized microdomains, were reported, and paroxysmal nocturnal hemoglobinuria (PNH), an acquired hematopoietic stem cell disorder, turned out to be caused by a defect of GPI biosynthesis. These findings drew the attention of many researchers. Thereafter, intensive studies were performed to reveal the biosynthetic pathway and biological significance of GPI and GPI-APs. This review focuses the recent progress in the field of mammalian GPI-APs.
Section snippets
Structure of GPI
During the following decade after the complete GPI-anchor structures in T. brucei of VSG [11] and rat Thy-1 [12] were reported in 1988, the partial and complete structures of GPI-anchors in more than 20 proteins became available. The results of these studies showed that the backbone structure was conserved among eukaryotes such as mammals, yeast (Saccharomyces cerevisiae), protozoan parasites (T. brucei and Plasmodium falciparum) and a plant species (Pyrus communis). The conserved backbone
Structural GPI remodeling in GPI-APs
This section focuses on the structural GPI remodeling that occurs after the GPI is transferred to the protein. Schemes for the overall structural remodeling of mammalian GPI-APs and the significance are shown in Fig. 2, Fig. 3. Defects in GPI biosynthesis abrogate the surface expression of GPI-APs, whereas these remodeling events may allow surface expression, but affect their trafficking, cellular localization or functions. As mentioned above, the backbone structure of the GPI moiety in the
Association of GPI-APs with lipid rafts
A body of evidence strongly indicates the presence of a physiologically specialized microdomain; however, there is still controversy about the definition and existence because of the difficulties in characterization due to their proposed small size and dynamic nature [96], [97], [98], [99]. Common assays using detergent extraction with cold non-ionic detergents, such as Triton X-100, and cholesterol depletion with methyl-β-cyclodextrin are indirect and not conclusive because of possible
Paroxysmal nocturnal hemoglobinuria; PNH
Several interesting findings reported around the 1990’s on the biological significance of GPI-APs, such as intracellular signaling [96], [112], [113], protein trafficking [91], [131] and the accumulation in specialized microdomains [91], [110] led to many researchers showing significant interest in this field. In the same period, the main pathology of paroxysmal nocturnal hemoglobinuria (PNH), an acquired hematopoietic stem cell disorder, was revealed. The main symptom of PNH is anemia due to
Conclusions and perspective
About a quarter of a century has passed since the concept of the GPI was established, and many proteins that operate in the GPI biosynthetic pathway in the ER have been identified. A large body of in vitro evidence indicates that GPIs are critical for the function and transport of GPI-APs by virtue of their unique physical nature, particularly the affinity for lipid rafts. Nevertheless, the functional in vivo significance of GPIs is poorly understood and the absence of detailed information is
Acknowledgement
This work was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References (225)
- et al.
Specific release of plasma membrane enzymes by a phosphatidylinositol-specific phospholipase C
Biochim Biophys Acta
(1978) - et al.
Identification of covalently bound inositol in the hydrophobic membrane-anchoring domain of Torpedo acetylcholinesterase
Biochem Biophys Res Commun
(1985) - et al.
Identification of covalently attached fatty acids in the hydrophobic membrane-binding domain of human erythrocyte acetylcholinesterase
Biochem Biophys Res Commun
(1985) - et al.
Trypanosoma brucei variant surface glycoprotein has a sn-1,2-dimyristyl glycerol membrane anchor at its COOH terminus
J Biol Chem
(1985) - et al.
Glycosyl-sn-1,2-dimyristylphosphatidylinositol is covalently linked to Trypanosoma brucei variant surface glycoprotein
J Biol Chem
(1985) - et al.
Human Smp3p adds a fourth mannose to yeast and human glycosylphosphatidylinositol precursors in vivo
J Biol Chem
(2004) - et al.
The glycosylation of the complement regulatory protein, human erythrocyte CD59
J Biol Chem
(1997) - et al.
A beta-N-acetylglucosaminyl phosphate diester residue is attached to the glycosylphosphatidylinositol anchor of human placental alkaline phosphatase: a target of the channel-forming toxin aerolysin
J Biol Chem
(2003) - et al.
Identification of molecular species of glycerophospholipids and sphingomyelin using electrospray mass spectrometry
J Lipid Res
(1994) - et al.
Lipid analysis of the glycoinositol phospholipid membrane anchor of human erythrocyte acetylcholinesterase. Palmitoylation of inositol results in resistance to phosphatidylinositol-specific phospholipase C
J Biol Chem
(1988)