Prenylation, lipid anchors

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. 

Fig. 5. Schematic representation of lipid anchors. The arrow heads and tails represent the N termini and the C termini of mature proteins, respectively, (a) Palmitoylation, (b) Ahnyristoylation, (c) Prenylation, (d) GPI anchor... 

Fig. 5.20. Membrane anchor of the heterotrimeric G-proteins. The lipid anchoring in the system of G-protein-conpled receptors and the corresponding G-proteins is shown. In the figure, it is assumed that the hpid anchors are located in the membrane. A possible involvement of the hpid anchor in protein-protein interactions is not shown. The G-protein-coupled receptor carries a pal-mitoic add anchor at the C-terminus. The a-subunit of the heterotrimeric G-protein is assodated with the membrane via a myristoic acid anchor at the N-terminus, whilst the y-subunit of the Py-complex uses a prenyl residue as a membrane anchor.

A third lipid anchor is provided by the polyprenyl farnesyl (15-carbon) and geranylgeranyl (20-carbon) groups in thioether linkage to cysteine residues. These must be present in specific recognition sequences at the C termini of proteins, most often with the sequence CAAX.211-215 The prenylation (also called isoprenyla-tion) reaction is followed by proteolytic removal of the last three residues (AAX) and methylation of the new C-terminal carboxyl group as is discussed in Chapter 11, Section D,3. See also Chapter 22, Section A,4. 

Most of the biological functions of the members of the Ras superfamily are linked to the cytoplasmic side of the cell membrane, where specific signals are received and transmitted further. Accordingly, Ras superfamily members contain structural features that mediate membrane association and serve as lipid anchors (see Section 3.7). Prenylation, palmitoylation and myristoylation are post-translational modifications frequently found on Ras superfamily members. 

Lipidation -acylation TV -myristoylation Myristoy-lation S-prenylation Prenylation Palmitoylation Isoprenylation GPI anchors Glypiation... 

PPCs Prenylation is the post-translational addition of 15- or 20-carbon isoprenyl lipids to the C-terminus of proteins. Prenylation is an irreverable modification that anchors proteins to the membrane fraction of cells. 

Membranes are asymmetric. Integral membrane proteins can t be washed off. Peripheral membrane proteins can be washed off. Membrane spanning segments and lipid modification (fatty acylation and prenylation), anchor proteins in a fluid bilayer (Singer fluid mosaic model). 

Inhibition of the lipid modification cascade provides an alternative way to block aberrant signaling pathways and that opportunity can be exploited in anticancer therapy. As part of the growth factor, signaling of the false activation is transmitted by the mutated ras gene encoded proteins (Ras) and ultimately leads to uncontrolled cell growth. These typical GTP binding proteins are also subject to membrane anchoring and the biosynthesis of those Ras proteins can be blocked at the posttranslational prenylation step. 

Prenylation (covalent attachment of an isoprenoid see Fig. 27-30) is a common mechanism by which proteins are anchored to the inner surface of cellular membranes in mammals (see Fig. 11-14). In some of these proteins the attached lipid is the 15-carbon farnesyl group others have the 20-carbon geranylgeranyl group. Different enzymes attach the two types of lipids. It is possible that prenylation reactions target proteins to different membranes, depending on which lipid is attached. Protein prenylation is another important role for the isoprene derivatives of the pathway to cholesterol. 

As already discussed, PLAP is concentrated In lipid rafts, the more ordered bIlayer microdomains that are enriched In sphingollpids and cholesterol (see Figure 5-10). Although PLAP and other GPTanchored proteins lie in the opposite membrane leaflet from acyl-anchored proteins, both types of membrane proteins are concentrated in lipid rafts. In contrast, prenylated proteins are not found in lipid rafts. 

Fig. 1. Structures of lipids covalently attached to proteins. Panel A shows proteins that are lipidated on cytoplasmi-cally exposed amino acids, whereas panel B shows lipidated proteins in the extracellular leaflet. (A) iV-myristoyl glycine, palmitate thioester-linked to cysteine, farnesyl, or geranylgeranyl (prenyl) thioether-linked to cysteine. (B) A/-palmitoyl cysteine, cholesterol ester-linked to glycine, and a minimal GPI anchor linked to the to amino acid in a GPI-anchored protein. The GPI structure is shown with a diacylglycerol moiety containing two ester-linked fatty acids. Other GPI anchors are based on ceramide, while yet others have monoacylglycerol, a fatty acid ether-linked to glycerol, and/or a fatty acid ester-linked to inositol.

Membrane anchoring of fatty acylated and prenylated proteins the two-signal hypothesis, lipid switches, and dynamic acylation... 

The four major types of protein lipidation are A-myristoylation, palmitoylation, prenylation and glycosylphosphatidylinositol-anchor (GPI-anchor) addition (Table 1). 

Ras proteins. Ras proteins are modified proteins associated with cell growth and the cell s response to insulin. They belong to a class of proteins called prenylated proteins, in which lipid groups derived from isoprenoid biosynthesis (Special Topic E, WileyPLUS) are appended as thioethers to C-terminal cysteine residues. Certain mutated forms of ras proteins cause oncogenic changes in various eukaryotic cell types. One effect of prenylation and other lipid modifications of proteins is to anchor these proteins to cellular membranes. Prenylation may also assist with molecular recognition of prenylated proteins by other proteins. ... 

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