Global Identification of Protein Prenyltransferase Substrates. Defining the Prenylated Proteome.

Corissa L. Lamphear, Elaina A. Zverina, James L. Hougland, Carol A. Fierke

Research output: Chapter in Book/Report/Conference proceedingChapter

6 Scopus citations

Abstract

The protein prenyltransferases, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase-I (GGTase-I), catalyze the attachment of a 15-carbon farnesyl or 20-carbon geranylgeranyl moiety, respectively, to a cysteine near the C-terminus of a substrate protein targeting it to the membrane. Substrates of the prenyltransferases are involved in a myriad of signaling pathways and processes within the cell, therefore inhibitors targeting FTase and GGTase-I are being developed as therapeutics for treatment of diseases such as cancer, parasitic infection, asthma, and progeria. FTase and GGTase-I were proposed to recognize a Ca 1 a 2 X motif, where C is the cysteine where the prenyl group is attached, a 1 and a 2 are small aliphatic amino acids, and X confers specificity between FTase and GGTase-I with X being methionine, serine, glutamine, and alanine for FTase and leucine or phenylalanine for GGTase-I. Recent studies indicate that the Ca 1 a 2 X paradigm should be expanded; therefore, further studies are needed to define the prenylated proteome, to understand normal cellular processes, and to determine the targets of prenyltransferase inhibitors. This review highlights the multiple approaches currently used to identify and define FTase and GGTase-I substrates. Direct identification approaches involve identifying FTase and GGTase-I substrates "one by one or by using lipid donor analogs. A complementary approach to identify the prenylated proteome is to define the modes of FTase and GGTase-I substrate recognition using structure-function studies, peptide library studies, and computational methods.

Original languageEnglish (US)
Title of host publicationEnzymes
PublisherAcademic Press
Pages207-234
Number of pages28
DOIs
StatePublished - 2011
Externally publishedYes

Publication series

NameEnzymes
Volume29
ISSN (Print)1874-6047

Keywords

  • Farnesylation
  • Geranylgeranylation
  • Prenylation
  • Protein farnesyltransferase
  • Protein geranylgeranyltransferase
  • Substrate specificity

ASJC Scopus subject areas

  • Biotechnology
  • Biophysics
  • Biochemistry
  • Molecular Biology

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  • Cite this

    Lamphear, C. L., Zverina, E. A., Hougland, J. L., & Fierke, C. A. (2011). Global Identification of Protein Prenyltransferase Substrates. Defining the Prenylated Proteome. In Enzymes (pp. 207-234). (Enzymes; Vol. 29). Academic Press. https://doi.org/10.1016/B978-0-12-381339-8.00012-3