Glypiation

Glypiation is the addition by covalent bonding of a glycosylphosphatidylinositol (GPI) anchor and is a common post-translational modification that localizes proteins to cell membranes. This special kind of glycosylation is widely detected on surface glycoproteins in eukaryotes and some Archaea.[1]

GPI anchors consist of a phosphoethanolamine linker that binds to the C-terminus of target proteins. Glycan's core structure has a phospholipid tail that anchors the structure to the membrane.

Both the lipid moiety of the tail and the sugar residues in the glycan core have considerable variation,[2][3][4][5][6][7] demonstrating vast functional diversity that includes signal transduction, cell adhesion and immune recognition.[8] GPI anchors can also be cleaved by enzymes such as phospholipase C to regulate the localization of proteins that are anchored at the plasma membrane.

Mechanism

Similar to the precursor glycan used for N-glycosylation, GPI anchor biosynthesis begins on the cytoplasmic leaflet of the ER and is completed on the luminal side. During this process, 3-4 Man and various other sugars (e.g., GlcNAc, Gal) are built onto a phosphatidylinositol (PI) molecule embedded in the membrane using sugars donated from sugar nucleotides and dolichol-P-mannose outside and inside the ER, respectively. Additionally, 2-3 phosphoethanolamine (EtN-P) linker residues are donated from phosphatidylethanolamine in the ER lumen to facilitate binding of the anchor to proteins.[9][10][11][12][13]

Proteins destined to be glypiated have two signal sequences:

GPIT does not have a consensus sequence but instead recognizes a C-terminal sequence motif that enables it to covalently attach a GPI anchor to an amino acid in the sequence. This C-terminal sequence is embedded in the ER membrane immediately after translation, and the protein is then cleaved from the sequence and attached to a preformed GPI anchor.[14][15]

Prediction of glypiation sites in proteins

In silico prediction of glypiation sites can be performed by:

References
  1. Kobayashi T. et al. (1997) The presence of GPI-linked protein(s) in an archaeobacterium, Sulfolobus acidocaldarius, closely related to eukaryotes. Biochim Biophys Acta. 1334, 1-4.
  2. Nosjean O. et al. (1997) Mammalian GPI proteins: Sorting, membrane residence and functions. Biochim Biophys Acta. 1331, 153-86.
  3. Thomas J. R. et al. (1990) Structure, biosynthesis, and function of glycosylphosphatidylinositols. Biochemistry. 29, 5413-22.
  4. Ikezawa H. (2002) Glycosylphosphatidylinositol (GPI)-anchored proteins. Biol Pharm Bull. 25, 409-17.
  5. Brewis I. A. et al. (1995) Structures of the glycosyl-phosphatidylinositol anchors of porcine and human renal membrane dipeptidase. Comprehensive structural studies on the porcine anchor and interspecies comparison of the glycan core structures. J Biol Chem. 270, 22946-56.
  6. Low M. G. (1989) Glycosyl-phosphatidylinositol: A versatile anchor for cell surface proteins. FASEB J. 3, 1600-8.
  7. Low M. G. and Saltiel A. R. (1988) Structural and functional roles of glycosyl-phosphatidylinositol in membranes. Science. 239, 268-75.
  8. Vainauskas S. and Menon A. K. (2006) Ethanolamine phosphate linked to the first mannose residue of glycosylphosphatidylinositol (GPI) lipids is a major feature of the GPI structure that is recognized by human GPI transamidase. J Biol Chem. 281, 38358-64.
  9. Menon A. K. et al. (1993) Phosphatidylethanolamine is the donor of the terminal phosphoethanolamine group in trypanosome glycosylphosphatidylinositols. EMBO J. 12, 1907-14.
  10. Menon A. K. et al. (1990) Biosynthesis of glycosyl-phosphatidylinositol lipids in Trypanosoma brucei: Involvement of mannosyl-phosphoryldolichol as the mannose donor. EMBO J. 9, 4249-58.
  11. Menon A. K. and Stevens V. L. (1992) Phosphatidylethanolamine is the donor of the ethanolamine residue linking a glycosylphosphatidylinositol anchor to protein. J Biol Chem. 267, 15277-80.
  12. Orlean P. (1990) Dolichol phosphate mannose synthase is required in vivo for glycosyl-phosphatidylinositol membrane anchoring, O mannosylation, and N glycosylation of protein in saccharomyces cerevisiae. Mol Cell Biol. 10, 5796-805.
  13. Imhof I. et al. (2000) Phosphatidylethanolamine is the donor of the phosphorylethanolamine linked to the alpha1,4-linked mannose of yeast GPI structures. Glycobiology. 10, 1271-5.
  14. Kinoshita T. et al. (1995) Defective glycosyl-phosphatidylinositol anchor synthesis and paroxysmal nocturnal hemoglobinuria. Adv Immunol. 60, 57-103.
  15. Udenfriend S. and Kodukula K. (1995) How glycosylphosphatidylinositol-anchored membrane proteins are made. Annu Rev Biochem. 64, 563-91.
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