title: Identification of a novel class of farnesylation targets by structure-based modeling of binding specificity.
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.
authors: Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Hadassah Medical School, The Hebrew University, Jerusalem, Israel.
authors: Nir
authors: N
authors: London
authors: Corissa L
authors: CL
authors: Lamphear
authors: James L
authors: JL
authors: Hougland
authors: Carol A
authors: CA
authors: Fierke
authors: Ora
authors: O
authors: Schueler-Furman
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D019295:Computational Biology; D030562:Databases, Protein; D051231:Farnesyltranstransferase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D051231:Farnesyltranstransferase