Protein glycosylation anchors

The first synthetic task assigned to an NPOE was the demanding glycosylation of an axial 2-OH group in the pseudotetrasaccharide 109, en route to the pseudopentasaccharide core of the protein membrane anchor found in Trypanosoma brucei that was obtained in 68% yield (Scheme 5.25) [76]. 

Four different types of lipid-anchoring motifs have been found to date. These are amide-linked myristoyl anchors, thioester-linked fatty acyl anchors, thioether-linked prenyl anchors, and amide-linked glycosyl phosphatidylinosi-tol anchors. Each of these anchoring motifs is used by a variety of membrane proteins, but each nonetheless exhibits a characteristic pattern of structural requirements. 

Low, M. G. The glycosyl-phosphatidyl anchor of membrane proteins. Biochim. Biophys. Acta. 988 4217-454,1989. 

Other pinocytotic pathways also exist that do not depend on either caveolae or clathrin, although these are not as well defined [55]. Specific receptors continue to be internalized in the absence of clathrin or caveolin and these pathways can be monitored by following glycosyl phos-phatidylinositol (GPI (-anchored proteins. Nonclathrin, noncaveolin pathways may also be responsible for the reuptake of membrane in neuroendocrine cells after stimulated secretion. Some, but not all, of these pathways appear to require dynamin. 

Caro, L., Tettelin, H., Vossen, J., Ram, A., van den Ende, H., and Klis, F. (1997). In silico identification of glycosyl-phosphatidylinositol-anchored plasma-membrane and cell wall proteins of Saccharomyces cerevisiae. Yeast 13, 1477—1489. 

PNH is caused by a mutation in certain types of adult blood cells. Because of this mutation, certain types of proteins, including complement inhibitors, are unable to attach to the surface of the cell, as is normally the case. More specifically, the PNH mutation prevents the assembly of a fatty tail, known as a glycosyl-phosphatidylinositol (GPI) anchor, a necessary step in surface attachment of some proteins. 

Type V and Vi proteins carry lipid anchors. These are fatty acids (palmitic acid, myristic acid), isoprenoids (e.g., farnesol), or glycoli-pids such as glycosyl phosphatidylinositol (GPi) that are covalently bound to the peptide chain. 

Figure 4-4. The domain organization of an integral, transmembrane protein as well as the mechanisms for interaction of proteins with membranes. The numbers illustrate the various ways by which proteins can associate with membranes I, multiple transmembrane domains formed of a-helices 2, a pore-forming structure composed of multiple transmembrane domains 3, a transmembrane protein with a single a-helical membrane-spanning domain 4, a protein bound to the membrane by insertion into the bilayer of a covalently attached fatty acid (from the inside) or 5, a glycosyl phosphatidylinositol anchor (from the outside) 6, a protein composed only of an extracellular domain and a membrane-embedded nonpolar tail 7, a peripheral membrane protein noncova-lently bound to an integral membrane protein.

GPI is an extracellular anchor for proteins. The GPI anchor consists of a phospholipid with an appended glycosyl and ethanolamme residue in a complicated arrangement (fig. 3.15). It is the most commonly employed anchor for the surface proteins of Trypa-... 

Some membrane proteins contain one or more covalently linked lipids of several types long-chain fatty acids, isoprenoids, sterols, or glycosylated derivatives of phosphatidylmositol, GPI (Fig. 11-14). The attached lipid provides a hydrophobic anchor that inserts into the lipid bilayer and holds the protein at the membrane surface. The strength of the hydrophobic interaction between a bilayer and a single hydrocarbon chain linked to a protein is barely enough to anchor the protein securely, but many proteins have more than one attached... 

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