Journal
BIOCHEMISTRY
Volume 44, Issue 46, Pages 15314-15324Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bi0509503
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Funding
- NIGMS NIH HHS [GM40602, T32 GM145304, T32 GM08353, GM07767] Funding Source: Medline
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Protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase 1) catalyze the attachment of lipid groups from farnesyl diphosphate and geranylgeranyl diphosphate, respectively, to a cysteine near the C-terminus of protein substrates. FTase and GGTase I modify several important signaling and regulatory proteins with C-terminal CaaX sequences (C refers to the cysteine residue that becomes prenylated, a refers to any aliphatic amino acid, and X refers to any amino acid). In the CaaX paradigm, the C-terminal X-residue of the protein/peptide confers specificity for FTase or GGTase I. However, some proteins, such as K-Ras, RhoB, and TC21, are substrates for both FTase and GGTase 1. Here we demonstrate that the C-terminal amino acid affects the binding affinity of K-Ras4B-derived hexapeptides (TKCVIX) to FTase and GGTase I modestly. In contrast, reactivity, as indicated by transient and steady-state kinetics, varies significantly and correlates with hydrophobicity, volume, and structure of the C-terminal amino acid. The reactivity of FTase decreases as the hydrophobicity of the C-terminal amino acid increases whereas the reactivity of GGTase I increases with the hydrophobicity of the X-group. Therefore, the hydrophobicity, as well as the structure of the X-group, determines whether peptides are specific for farnesylation, geranylgeranylation, or dual prenylation.
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