Structure of mammalian protein geranylgeranyltransferase type-I.
Protein geranylgeranyltransferase type-I (GGTase-I), one of two CaaX prenyltransferases, is an essential enzyme in eukaryotes. GGTase-I catalyzes C-terminal lipidation of >100 proteins, including many GTP- binding regulatory proteins. We present the first structural information for mammalian GGTase-I, including a series of substrate and product complexes that delineate the path of the chemical reaction. These structures reveal that all protein prenyltransferases share a common reaction mechanism and identify specific residues that play a dominant role in determining prenyl group specificity. This hypothesis was confirmed by converting farnesyltransferase (15-C prenyl substrate) into GGTase-I (20-C prenyl substrate) with a single point mutation. GGTase-I discriminates against farnesyl diphosphate (FPP) at the product turnover step through the inability of a 15-C FPP to displace the 20-C prenyl-peptide product. Understanding these key features of specificity is expected to contribute to optimization of anti-cancer and anti-parasite drugs.
Taylor
Jeffrey S
JS
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Reid
T Scott
TS
Terry
Kimberly L
KL
Casey
Patrick J
PJ
Beese
Lorena S
LS
D019883:Alkyl and Aryl Transferases / Q000737:chemistry*; D000595:Amino Acid Sequence; D001665:Binding Sites; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013379:Substrate Specificity
D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase