Identification of a novel class of farnesylation targets by structure-based modeling of binding specificity

Nir London, Corissa L. Lamphear, James L Hougland, Carol A. Fierke, Ora Schueler-Furman

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Farnesylation is an important post-translational modification catalyzed by farnesyltransferase (FTase). Until recently it was believed that a C-terminal CaaX motif is required for farnesylation, but recent experiments have revealed larger substrate diversity. In this study, we propose a general structural modeling scheme to account for peptide binding specificity and recapitulate the experimentally derived selectivity profile of FTase in vitro. In addition to highly accurate recovery of known FTase targets, we also identify a range of novel potential targets in the human genome, including a new substrate class with an acidic C-terminal residue (CxxD/E). In vitro experiments verified farnesylation of 26/29 tested peptides, including both novel human targets, as well as peptides predicted to tightly bind FTase. This study extends the putative range of biological farnesylation substrates. Moreover, it suggests that the ability of a peptide to bind FTase is a main determinant for the farnesylation reaction. Finally, simple adaptation of our approach can contribute to more accurate and complete elucidation of peptide-mediated interactions and modifications in the cell.

Original languageEnglish (US)
Article numbere1002170
JournalPLoS Computational Biology
Volume7
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Farnesyltranstransferase
Prenylation
Peptides
peptide
Specificity
peptides
Target
Modeling
modeling
Substrate
substrate
Substrates
Structural Modeling
post-translational modification
Human Genome
Post Translational Protein Processing
Selectivity
Range of data
Experiment
Determinant

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Ecology
  • Molecular Biology
  • Genetics
  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Computational Theory and Mathematics

Cite this

Identification of a novel class of farnesylation targets by structure-based modeling of binding specificity. / London, Nir; Lamphear, Corissa L.; Hougland, James L; Fierke, Carol A.; Schueler-Furman, Ora.

In: PLoS Computational Biology, Vol. 7, No. 10, e1002170, 10.2011.

Research output: Contribution to journalArticle

London, Nir ; Lamphear, Corissa L. ; Hougland, James L ; Fierke, Carol A. ; Schueler-Furman, Ora. / Identification of a novel class of farnesylation targets by structure-based modeling of binding specificity. In: PLoS Computational Biology. 2011 ; Vol. 7, No. 10.
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