Glypiation

Glypiation is the covalent bond 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 has 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:

• An N-terminal signal sequence that directs co-translational transport into the ER
• A C-terminal signal sequence that is recognized by a GPI transamidase (GPIT)^[8]

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:

• GPI-SOM: Identification of GPI-anchor signals by a Kohonen Self Organizing Map
• PredGPI: a GPI-anchor predictor
• big-PI Predictor - GPI Modification Site Prediction
• FragAnchor: GPI-Anchored Protein Prediction Tandem System (NN+HMM)
• MemType-2L

References