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 p21ras 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.