Structure of mammalian protein geranylgeranyltransferase type-I.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Taylor, JS; Reid, TS; Terry, KL; Casey, PJ; Beese, LS

Published Date

  • November 17, 2003

Published In

Volume / Issue

  • 22 / 22

Start / End Page

  • 5963 - 5974

PubMed ID

  • 14609943

Pubmed Central ID

  • 14609943

International Standard Serial Number (ISSN)

  • 0261-4189

Digital Object Identifier (DOI)

  • 10.1093/emboj/cdg571

Language

  • eng

Conference Location

  • England