#glycosylphosphatidylinositol

Glycolipid and Phospholipid

What is the primary function of glycosylphosphatidylinositol (GPI) anchors?

GPI anchoring represents post translational modification replacing C terminal transmembrane domain with glycolipid tether enabling raft association regulated release and apical sorting. Synthesis begins ER cytoplasmic leaflet adding GlcNAc phosphatidylinositol, deacetylation, flipping lumen, mannose three additions PIGM PIGB PIGV, phosphoethanolamine PIGN PIGO, attachment protein by transamidase complex PIGK GAA1 PIGS PIGT PIGU removing C terminal signal peptide forming amide bond ethanolamine phosphate mannose. Fatty acid remodeling PGAP1 PGAP3 generates saturated chains favoring ordered doma

Ref: Kinoshita T., Biochim Biophys Acta 2020, GPI anchor biosynthesis protein tethering raft.

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Lipid Link Protein

In GPI anchoring, what is the nature of the bond between the protein and the lipid?

Glycosylphosphatidylinositol anchoring provides mode of attaching otherwise soluble proteins to extracellular face of plasma membrane. Biosynthesis in endoplasmic reticulum assembles GPI precursor containing phosphatidylinositol with two acyl chains inserted in lumenal leaflet, glucosamine, three mannoses and phosphoethanolamine moieties. Transamidase complex cleaves C-terminal GPI signal peptide at omega site and forms amide bond between new C-terminal carboxyl and amine of terminal ethanolamine phosphate which is glycosidically linked to mannose alpha1-2-mannose core. Further glycosidic bond

Ref: Kinoshita, J Lipid Res 2020, GPI anchor structure; Fujita & Kinoshita 2012.

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Lipid Link Protein

The lipid anchor in GPI-anchored proteins is attached to which part of the protein?

Glycosylphosphatidylinositol anchoring is complex post-translational modification processed in endoplasmic reticulum for about 150 human proteins destined for extracellular leaflet. Nascent proteins contain C-terminal hydrophobic signal peptide that is recognized by transamidase complex, cleaved after a specific omega residue, and replaced en bloc with preformed GPI moiety consisting of phosphatidylinositol lipid, glucosamine, three mannoses, phosphoethanolamine and galactose modifications. Attachment occurs to new C-terminus via amide linkage between protein carboxyl group and ethanolamine ph

Ref: Fujita & Kinoshita, J Lipid Res 2012, GPI anchor biosynthesis and attachment.

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Protein Sorting and Trafficking

GPI-anchored proteins are synthesized in:

Glycosylphosphatidylinositol anchoring provides alternative membrane attachment without transmembrane span, enabling rapid lateral diffusion within lipid rafts, apical sorting and regulated release by phospholipases. Precursors contain N-terminal ER targeting signal and C-terminal GPI attachment signal comprising small residues at omega cleavage site followed by moderately polar spacer and hydrophobic tail of fifteen to twenty residues. Co-translationally inserted into ER lumen via Sec61, nascent chain may receive N-glycans, then GPI transamidase complex, pentamer of PIG-K catalytic cysteine p

Ref: Kinoshita T, Annu Rev Biochem 89: 2020, GPI-Anchored Protein Biosynthesis in ER.

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