CAAX protein prenylation

Fu, H.W., and Casey, P.J. (1999). Enzymology and biology of CaaX protein prenylation. Recent Prog Harm Res 54 315-342, discussion 342-313. 

The first step of the series of modifications involved in the processing of CAAX-type prenyl proteins occurs in the cytoplasm, catalyzed by either protein farnesyltransferase (FTase) or protein geranylgeranyltransferase type I (GGTase-I). The specificity for either of these two enzymes for the most part depends on the identity of the last amino acid X of the CAAX consensus sequence. When X is serine, cysteine, alanine, or glutamine, the 15 carbon farnesyl group is added to the cysteine catalyzed by FTase and when X is leucine, the 20 carbon geranylgeranyl group is added by... 

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. 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. 

Subsequent to prenyl modification, Ras and most other CaaX proteins are further processed by two endoplasmic reticulum (ER)-localized, membrane-bound enzymes. The first prenyl-dependent processing step is the proteolytic removal of the -aaX tripeptide by the CaaX protease Reel this is followed by carboxymethylation of the now C-terminal prenylcysteine residue by the methyltransferase Icmt (Fig. 2). The result of these modifications is to produce a protein that exhibits some affinity for cellular membranes and also to impart a unique structure at the C-terminus that can serve as a specific recognition motif in certain protein-protein interactions. 

S-geranylgeranylation. They are similar in their behavior, but they differ in specificity with regards to the C-terminal sequence of proteins. Prenylation can be performed via covalent attachment of either Cis famesyl or C20 geranylgeranyl moiety to the cysteine residue of CAAX motif present in the protein to be modified (A aliphatic amino acid, X variable residue) [L. A. Beck et al.. Cell Biol. 1988,107,1307 F. L. Zhang, P. J. Casey, Annu. Rev. Biochem. 1996, 65, 241 D. M. Leonard, J. Med. Chem. 1997, 40, 2971]. 

FIGURE 9.19 Proteins containing the C-terminal sequence CAAX can undergo prenylation reactions that place thioether-linked farnesyl or geranylgeranyl groups at the cysteine side chain. Prenylation is accompanied by removal of the AAX peptide and methylation of the carboxyl group of the cysteine residue, which has become the C-terminal residue. 

The y-subunit contains a characteristic CAAX motif, which allows covalent attachment of prenyl groups and anchors the protein to the inner surface of the membrane. 

Studying the sequences of farnesylated proteins indicated that all lipidated proteins bear a cysteine residue near the C-terminus revealing the CAAX-motif, where C is a cysteine, A stands for an aliphatic amino acid, and X can be any amino acid. Database searches resulted in more prenylated proteins, all bearing the CAAX-motif, in systems from lower eukaryotes to mammals. A closer look at the mature proteins revealed that prenylation was only the first step of processing of the CAAX-motif-encoded proteins. After transfer of the isoprene unit, the last three amino acids are cleaved proteolytically by an endoprotease and the C-terminal cysteine is carboxymethylated by a methyltransferase. ... 

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