Towards Complete Sets of Farnesylated and Geranylgeranylated Proteins

Abstract

Three different prenyltransferases attach isoprenyl anchors to C-terminal motifs in substrate proteins. These lipid anchors serve for membrane attachment or protein–protein interactions in many pathways. Although well-tolerated selective prenyltransferase inhibitors are clinically available, their mode of action remains unclear since the known substrate sets of the various prenyltransferases are incomplete. The Prenylation Prediction Suite (PrePS) has been applied for large-scale predictions of prenylated proteins. To prioritize targets for experimental verification, we rank the predictions by their functional importance estimated by evolutionary conservation of the prenylation motifs within protein families. The ranked lists of predictions are accessible as PRENbase (http://mendel.imp.univie.ac.at/sat/PrePS/PRENbase) and can be queried for verification status, type of modifying enzymes (anchor type), and taxonomic distribution. Our results highlight a large group of plant metal-binding chaperones as well as several newly predicted proteins involved in ubiquitin-mediated protein degradation, enriching the known functional repertoire of prenylated proteins. Furthermore, we identify two possibly prenylated proteins in Mimivirus. The section HumanPRENbase provides complete lists of predicted prenylated human proteins—for example, the list of farnesyltransferase targets that cannot become substrates of geranylgeranyltransferase 1 and, therefore, are especially affected by farnesyltransferase inhibitors (FTIs) used in cancer and anti-parasite therapy. We report direct experimental evidence verifying the prediction of the human proteins Prickle1, Prickle2, the BRO1 domain–containing FLJ32421 (termed BROFTI), and Rab28 (short isoform) as exclusive farnesyltransferase targets. We introduce PRENbase, a database of large-scale predictions of protein prenylation substrates ranked by evolutionary conservation of the motif. Experimental evidence is presented for the selective farnesylation of targets with an evolutionary conserved modification site.

Computational analysis of the human HSPH/HSPA/DNAJ family and cloning of a human HSPH/HSPA/DNAJ expression library

“…For all predictors, the default settings for mammalian or animal proteins were used. The presence of prenelation motifs was determined using the PrePS webserver (Maurer-Stroh et al 2007). …”

Prenylation defects in inherited retinal diseases

“…More than 100 proteins, collectively called the prenylome, are involved in the molecular pathways producing these lipid moieties, or serve as potential substrates for prenylation 5. PRENbase (http://mendel.imp.ac.at/PrePS/PRENbase/, date accessed 22 October 20136). …”

Farnesyltransferase Inhibitors: A Detailed Chemical View on an Elusive Biological Problem

“…However, substrate specificity is in no way absolute and the existence of cross-prenylation has been proved possible [15][16][17]. In fact, a recent study, which applied amino acid sequence-based predictors for various types of protein prenylation over the National Center for Biotechnology Institute's (NCBI) nonredundant protein sequence database, has estimated in 1674 the number of proteins that can be subject to prenylation by both FTase and GGTase I, a value that represents something like 40% of the total predicted number of possible FTase targets (3998 proteins) [18]. Globally, something like 0.5% of all proteins in animals are thought to be prenylated [19], with geranylgeranylation being 5-10-fold more common than farnesylation [20,21].…”

“…Globally, something like 0.5% of all proteins in animals are thought to be prenylated [19], with geranylgeranylation being 5-10-fold more common than farnesylation [20,21]. Examples of known FTase targets include the H-, N-, and K-ras proteins, nuclear lamins A and B, the subunit of heterotrimeric G-proteins, and several proteins involved in visual signal transduction, whereas RhoA, cdc42, Rap1, Rac1, R-ras and TC-21 are among the identified GGTase I substrates [14,18,[22][23][24].…”