Abstract
Glycosylphosphatidylinositol (GPI) anchoring of cell surface proteins is the most complex and metabolically expensive of the lipid posttranslational modifications described to date. The GPI anchor is synthesized via a membrane-bound multistep pathway in the endoplasmic reticulum (ER) requiring >20 gene products. The pathway is initiated on the cytoplasmic side of the ER and completed in the ER lumen, necessitating flipping of a glycolipid intermediate across the membrane. The completed GPI anchor is attached to proteins that have been translocated across the ER membrane and that display a GPI signal anchor sequence at the C terminus. GPI proteins transit the secretory pathway to the cell surface; in yeast, many become covalently attached to the cell wall. Genes encoding proteins involved in all but one of the predicted steps in the assembly of the GPI precursor glycolipid and its transfer to protein in mammals and yeast have now been identified. Most of these genes encode polytopic membrane proteins, some of which are organized in complexes. The steps in GPI assembly, and the enzymes that carry them out, are highly conserved. GPI biosynthesis is essential for viability in yeast and for embryonic development in mammals. In this review, we describe the biosynthesis of mammalian and yeast GPIs, their transfer to protein, and their subsequent processing.
Highlights
Glycosylphosphatidylinositol (GPI) anchoring of cell surface proteins is the most complex and metabolically expensive of the lipid posttranslational modifications described to date
1% of all proteins encoded by eukaryotic genomes, or ?10–20% of all membrane proteins that enter the secretory pathway after being targeted to the endoplasmic reticulum (ER), are posttranslationally modified at their C terminus by glycosylphosphatidylinositol (GPI), a complex glycophospholipid that serves to anchor proteins to the cell surface
The importance of GPI anchoring in mammals is underscored by the facts that abrogation of GPI biosynthesis results in embryonic lethality [1] and that an inherited hypomorphic promoter mutation that decreases the expression of the mannosyltransferase PIG-M and impairs GPI mannosylation leads to thromboses of the portal and hepatic veins as well as seizures [2]
Summary
Detailed analyses of the structures of protein-bound GPIs from mammals, protozoa, and yeast [17,18,19,20,21,22] reveal that they have a conserved core structure: protein-CONH2-CH2-CH2-PO4-6-Mana1,2Mana1,6Mana1,4GlcNa1, 6-myo-inositol phospholipid (Fig. 1A). The inositol acyl group is normally removed in the ER after transfer of the GPI to protein, and remodeling of the diacylglycerol moiety present on the GPI precursor that is transferred to protein likewise is initiated in the ER and continued in the Golgi (see below). Protein-bound GPIs in both yeast and mammals can bear Etn-P on Man-1 [20, 24], but it is not clear whether this substituent is invariably retained or whether it can be removed from certain GPIs after anchor transfer to protein. The fate of Etn-P moieties added to Man-2 of GPI precursors is unknown
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