Prenylation of ras and ras-Related Proteins

Abstract

In common with certain other cellular proteins, a CAAX motif (C=cysteine, A=Aliphatic, X=any amino acid) is found at the C-terminus of all ras proteins. This motif undergoes a triplet of closely coupled post-translational modifications. First, a prenoid derivative is linked as a thioether to the cysteine residue (Hancock et al,1989; Casey et al,1989), second, the -AAX amino acids are removed by proteolysis (Gutierriez et al,1989) and third, the α-carboxyl group of the now C-terminal cysteine residue is methyl-esterified (Clarke et al,1988; Gutierrez et al,1989). Although the p21^ras proteins, the nuclear lamins A and B and the γ-subunit of transducin (Fukada et al, 1990: Lai et al, 1990) are all prenylated with C₁₅ farnesyl, prenylation of proteins with C₂₀ geranylgeranyl is some 10x more common than farnesylation (Epstein et al, 1990). Recently, certain CAAX containing proteins have been identified which are geranylgeranylated, these include the γ-subunits of brain G-proteins (Yamane et al,1990; Mumby et al,1990) and the ras-related proteins Krev1/rap1A (Kawata et al,1990; Buss et al,1991) and G25K (Maltese and Sheridan, 1990). A common feature of the CAAX motifs of these C₂₀ modified proteins is the presence of a leucine residue in the X position. This raises the possibility that the X amino acid determines which isoprenoid residue is used to prenylate a CAAX motif. In addition to the prenylation of CAAX boxes, it is likely that the ras-related rab proteins, which terminate in CC or CXC motifs, might also undergo prenylation since it is known that for these proteins the C-terminal cysteines are essential for function.