Lipid-anchored proteins

A large number of integral proteins in eukaryotes do not traverse the membrane but are anchored in one or other leafiet of the bilayer through covalent attachment to a hydrocarbon chain. Various proteins, involving the prion protein the causative  agent  of  mad  cow  disease  are  stably anchored  at  the  cell  surface through  covalent  linkage  of their  C-terminal  amino  acid  to the  headgroup  of a   phosphatidylinositol   lipid   through   an   ethanolamine–phosphate–trimannose–glucosamine   bridge,  so-called GPI (glycosyl  phosphatidylinositol)-anchored proteins. This complex structure is built up by sequential addition of the individual sugar residues and ethanolamine phosphate to phosphatidylinositol. The C-terminal hydrophobic signal peptide is erased from the protein in the lumen of the RER and the preformed GPI anchor added to the latest exposed C- terminal amino acid.

Another proteins are transiently  attached to the cytosolic face of the membrane either  through amide  linkage  of a myristate  C14:0 molecule  to an N-terminal  Gly residue or through thioether  linkage of a 15-carbon farnesyl  or a 20-carbon  geranylgeranyl  polyunsaturated  hydrocarbon  to a C- terminal Cys residue (prenylated  proteins). Farnesyl and geranylgeranyl are synthesized from isopentenyl pyrophosphate and the precursor of cholesterol

Figure: Lipid-modified proteins. (a) A glycosyl phosphatidylinositol-anchored protein (G, glucosamine; M, mannose; EtP, ethanolamine phosphate); (b) a myristoylated protein; (c) a prenylated protein; (d) a palmitoylated protein.

(See Topic K5). Some proteins are also modified on Cys residues with covalently attached palmitate (C16:0) (palmitoylated proteins). These include some with membrane-spanning polypeptides (Fig. 2d), some prenylated proteins and some myristoylated  proteins. Several of the proteins included in cell signaling, like as the G proteins and the Ras family of proteins are lipid modified.