Therapeutic intervention based on protein prenylation and associated modifications

Abstract

In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

“…Here we show that the CaaX-processing enzymes are dually localized to the INM, in addition to their previously characterized ER membrane localization. Our data reconciles the paradox surrounding nuclear lamin A processing, and indicates that the nucleus is a CaaXprocessing compartment, in addition to the ER membrane where Ras, Rho, a-factor, and other CaaX proteins are known to be modified (Gelb et al, 2006;Wright and Philips, 2006). Our findings provide a mechanistic and logistical basis for earlier evidence suggesting that the nuclear import of prelamin A via its strong NLS precedes its processing (Lehner et al, 1986;Lutz et al, 1992;Sasseville and Raymond, 1995).…”

“…It is notable that B-type lamins do not undergo endoproteolytic cleavage by Zmpste24 and retain their CaaX modifications, whereas lamin C (a splice variant of the lamin A/C gene) lacks a CaaX motif and is not modified at all. Most proteins undergo farnesylation in the cytosol and postprenylation CaaX processing at the cytosolic face of the ER (Winter-Vann and Casey, 2005;Gelb et al, 2006). CaaX proteins that are processed by these enzymes have a variety of final intracellular localizations.…”

“…Most proteins undergo farnesylation in the cytosol and postprenylation CaaX processing at the cytosolic face of the ER (Winter-Vann and Casey, 2005;Gelb et al, 2006). CaaX proteins that are processed by these enzymes have a variety of final intracellular localizations.…”

“…CaaX processing constitutes a series of posttranslational modifications for a subset of cellular proteins (e.g., the oncoprotein Ras, the nuclear lamins, and the yeast mating pheromone a-factor) that contain a C-terminal CaaX motif (C, cysteine, a, aliphatic amino acid, X, any amino acid; Zhang and Casey, 1996;Young et al, 2005;Wright and Philips, 2006). CaaX processing affects the membrane binding affinity, localization, and functional activity of proteins (Gelb et al, 2006). This processing pathway is shown in the context of the mammalian nuclear scaffold protein lamin A in Figure 1A, steps 1-3.…”

Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria

“…4F–J). Previous literatures reported that releasing progerin from the nuclear membrane by farnesyltransferase inhibitor treatment partially rescued the gene expression and morphological defects in HGPS cells (Capell et al ., 2005, 2008; Capell & Collins, 2006; Gelb et al ., 2006; Cao et al ., 2007; Wang et al ., 2007; Marji et al ., 2010). Indeed, we find that not only the nuclear morphology but also the chromatin organization and gene expression are improved in the MB‐treated HGPS nucleus (Fig.…”