Cholesterol binding motif

Although the third amino acid that defines the CRAC domain (Lys-79 or Lys-81 in this case) is not directly involved in cholesterol binding, it stabilizes the orientation of Tyr-77, resulting in a remarkable fit of cholesterol for this CRAC domain. This interaction illustrates how well the algorithm performs. Nevertheless, the whole motif is rather polar than apolar because the nondefined X residues of this CRAC domain are chiefly arginine and lysine. Consequently, this domain is not located inside the membrane, but in the cytoplasm. Thus, despite the fact that this domain can theoretically bind cholesterol with high affinity, as correctly predicted by the CRAC algorithm, its location outside the membrane precludes any functional interaction with membrane cholesterol. 

FIGURE 6.8 The sphingomyelin-binding motif for transmembrane domains. (A) Docking of cholesterol onto... 

FTase catalyzes the covalent attachment of a farnesyl moiety via a thioether Unkage to the proteins bearing a C-terminal amino acid sequence known as the CAAX motif (Fig. 2) [12,21]. The farnesyl moiety is derived from farnesyl pyrophosphate (FPP), a 15-carbon isoprenyl intermediate in the mevalonate pathway of cholesterol biosynthesis. The binding of FPP to the enzyme has relatively high affinity (K = 1-lOnM), and FPP binding must precede the binding of the peptide substrate for successful catalysis [22,23]. 

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