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PubMed2003

Treating dyslipidemia with statins: the risk-benefit profile.

BACKGROUND: Coronary heart disease (CHD), the result of coronary atherosclerosis, is the largest single killer of Americans. Central to the pathogenesis of atherosclerosis are the deposition and retention of cholesterol in the arterial walls. Lipid modification, therefore, is key to CHD prevention. METHODS: Data from trials evaluating the safety and efficacy of several pharmacologic agents for dyslipidemia were thoroughly reviewed. RESULTS: Agents such as bile acid sequestrants, fibric acids, and nicotinic acid have a role in treating dyslipidemia. However, statins are the safest and most effective of the lipid-modifying drugs, reducing the incidence of CHD by as much as 21% to 43%. Despite the overall safety and efficacy of these agents, many patients undergoing statin therapy fail to achieve the treatment goals specified in the National Cholesterol Education Program Adult Treatment Panel III guidelines, often because of suboptimal use, tolerability problems, or lack of compliance. Although adverse effects of statins are generally mild and transient, more serious adverse effects, including myotoxicity, liver toxicity, and rhabdomyolysis, are still possible with statin monotherapy and are more common in patients receiving concomitant therapy with other drugs metabolized by the cytochrome P-450 enzyme system. CONCLUSIONS: Because of the overall safety and efficacy of the statins, more patients with or at risk for CHD should be receiving aggressive therapy to lower low-density lipoprotein cholesterol levels and reduce CHD risk.

Atorvastatin↗
PubMed1996

Novel determinants of H-Ras plasma membrane localization and transformation.

Although it is well-established that modification of Ras by farnesol is a critical step for its membrane association and transforming activity, the contribution of other C-terminal sequences and palmitate modification to Ras localization and function remains unclear. We have characterized H-Ras mutant proteins with alterations in the palmitoylated cysteines or in sequences flanking these residues. We found that non-palmitoylated proteins were impaired not only in membrane association but also in transforming activity. Mutations which drastically altered residues adjacent to the palmitoylated cysteine did not abolish palmitoylation. However, despite continued lipid modification the mutant proteins failed to bind to plasma membranes and instead accumulated on internal membranes and, importantly, were not transforming. Addition of an N-terminal myristoylation signal to these defective mutants, or to proteins entirely lacking the C-terminal 25 residues restored both plasma membrane association and transforming activity. Thus, H-Ras does not absolutely require prenylation or palmitoylation nor indeed its hypervariable domain in order to interact with effectors that ultimately cause transformation. However, in this native state, the C-terminus appears to provide a combination of lipids and a previously unrecognized signal for specific plasma membrane targeting that are essential for the correct localization and biological function of H-Ras.

Animals↗
PubMed2006

Lipid-protein interactions in GPCR-associated signaling.

Signal transduction via G-protein-coupled receptors (GPCRs) is a fundamental pathway through which the functions of an individual cell can be integrated within the demands of a multicellular organism. Since this family of receptors first discovered, the proteins that constitute this signaling cascade and their interactions with one another have been studied intensely. In parallel, the pivotal role of lipids in the correct and efficient propagation of extracellular signals has attracted ever increasing attention. This is not surprising given that most of the signal transduction machinery is membrane-associated and therefore lipid-related. Hence, lipid-protein interactions exert a considerable influence on the activity of these proteins. This review focuses on the post-translational lipid modifications of GPCRs and G proteins (palmitoylation, myristoylation, and isoprenylation) and their significance for membrane binding, trafficking and signaling. Moreover, we address how the particular biophysical properties of different membrane structures may regulate the localization of these proteins and the potential functional consequences of this phenomenon in signal transduction. Finally, the interactions that occur between membrane lipids and GPCR effector enzymes such as PLC and PKC are also considered.

Cell Membrane↗
PubMed2002

Lipid management in diabetic patients: lessons from prevention trials.

Diabetes is associated with greatly enhanced risk for coronary heart disease (CHD), a correlation that justifies aggressive risk intervention in diabetic individuals. Lipid abnormalities in diabetes frequently consist of elevated triglyceride and low-density lipoprotein cholesterol levels and low high-density lipoprotein cholesterol levels. Subgroup analyses of primary and secondary prevention trials with fibrates and statins indicate that lipid modification in diabetic patients is associated with significant CHD risk reduction. In 1 angiographic study (Diabetes Atherosclerosis Intervention Study) fibrate treatment was shown to reduce the rate of atherosclerotic progression. A primary prevention study of statin treatment (West of Scotland Coronary Prevention Study) showed reduced risk for progression to diabetes in a post hoc analysis. Optimal lipid-modifying treatment in individuals with diabetes remains to be defined. Upcoming trials with diabetic cohorts will improve our understanding of how lipid treatment affects CHD risk in this patient population.

Clinical Trials as Topic↗
PubMed2000

Cellular lipid composition influences stress activation of the yeast general stress response element (STRE).

The heat inducibility of the yeast heat-shock response (HSR) pathway has been shown to be critically dependent on the level of unsaturated fatty acids present in the cell. Here the inducibility by heat or salt of the independently regulated general stress response (GSR) pathway is shown to be affected in the same way. An increase in the percentage of unsaturated fatty acids in heat- or salt-acclimated cells correlated with a decrease in the induction of a general stress-response-promoter-element (STRE)-driven reporter gene by either stress. Despite inducing reporter gene expression, sorbic acid treatment did not confer salt cross-tolerance on the cells. This failure correlated with a failure to increase the percentage of unsaturated fatty acids in the cells, suggesting that GSR pathway induction, in the absence of lipid changes, is insufficient for the induction of cross-tolerance. Cells grown with fatty acid supplements under anaerobic conditions provided further evidence for a potential role for lipids in the acquisition of stress resistance. These cells contained different fatty acid profiles depending on the fatty acid supplement supplied, exhibited differential sensitivity to both heat and salt stress, but had not undergone STRE induction. These results suggest that heat- and salt-stress induction of the GSR are sensitive to the level of unsaturated fatty acids present in the cell and that stress cross-tolerance may be a lipid-mediated phenomenon. Given that an increased level of unsaturated fatty acids also down-regulates heat induction of the HSR pathway, these observations lead to the provocative hypothesis that lipid modifications, rather than HSR or GSR pathway induction, are a major contributor to the induced heat and salt tolerance of yeast cells.

Adaptation, Biological↗
PubMed2001

Protein farnesyltransferase isoprenoid substrate discrimination is dependent on isoprene double bonds and branched methyl groups.

Farnesylation is a posttranslational lipid modification in which a 15-carbon farnesyl isoprenoid is linked via a thioether bond to specific cysteine residues of proteins in a reaction catalyzed by protein farnesyltransferase (FTase). We synthesized the benzyloxyisoprenyl pyrophosphate (BnPP) series of transferable farnesyl pyrophosphate (FPP) analogues (1a-e) to test the length dependence of the isoprenoid substrate on the FTase-catalyzed transfer of lipid to protein substrate. Kinetic analyses show that pyrophosphates 1a-e and geranyl pyrophosphate (GPP) transfer with a lower efficiency than FPP whereas geranylgeranyl pyrophosphate (GGPP) does not transfer at all. While a correlation was found between K(m) and analogue hydrophobicity and length, there was no correlation between k(cat) and these properties. Potential binding geometries of FPP, GPP, GGPP, and analogues 1a-e were examined by modeling the molecules into the active site of the FTase crystal structure. We found that analogue 1d displaces approximately the same volume of the active site as does FPP, whereas GPP and analogues 1a-c occupy lesser volumes and 1e occupies a slightly larger volume. Modeling also indicated that GGPP adopts a different conformation than the farnesyl chain of FPP, partially occluding the space occupied by the Ca(1)a(2)X peptide in the ternary X-ray crystal structure. Within the confines of the FTase pocket, the double bonds and branched methyl groups of the geranylgeranyl chain significantly restrict the number of possible conformations relative to the more flexible lipid chain of analogues 1a-e. The modeling results also provide a molecular explanation for the observation that an aromatic ring is a good isostere for the terminal isoprene of FPP.

Alkyl and Aryl Transferases↗
PubMed1995

Program on the surgical control of the hyperlipidemias: 1994 report.

The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, tested the hypothesis that cholesterol modification induced by partial ileal bypass would favorably affect mortality and morbidity due to coronary heart disease (CHD). The study population consisted of 838 patients (417 in the control group and 421 in the surgery group) in four clinical centers, both men (90.7%) and women with an average age of 51 years who had survived a first myocardial infarction. The lipid changes in POSCH have been the most marked in any atherosclerosis intervention trial utilizing a single mode of intervention in addition to diet therapy. At 5 years, the surgery group, compared with the control group, had a 23.3 +/- 1.0% (mean +/- SE) lower total plasma cholesterol level (p < 0.0001), a 37.7 +/- 1.2% lower low-density lipoprotein cholesterol level (p < 0.0001), and a 4.3 +/- 1.8% higher high-density lipoprotein cholesterol level (p = 0.02). For the combined end point of CHD mortality and confirmed nonfatal myocardial infarction, there was a 35.0% reduction in the surgery group (p < 0.001). Coronary artery bypass grafting was reduced in the surgery group by 62.0% (p < 0.0001) and percutaneous transluminal coronary angioplasty was reduced by 55.0% (p < 0.01). A comparison of baseline coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less atherosclerosis disease progression (p < 0.001) and greater atherosclerosis disease regression at 5 and 7 years (p < 0.01) in the surgery group. At formal trial completion in July 1990, the overall mortality in the surgery subgroup with an ejection fraction of 50% or greater was 36.1% lower (p = 0.02). During subsequent follow-up, trends toward statistical significance for differences in both CHD and in overall mortality have become evident. The POSCH results provide strong support for beneficial clinical and arteriographic reduction of atherosclerosis progression after lipid modification by partial ileal bypass.

Adult↗
PubMed2001

All phox homology (PX) domains from Saccharomyces cerevisiae specifically recognize phosphatidylinositol 3-phosphate.

Phox homology (PX) domains are named for a 130-amino acid region of homology shared with part of two components of the phagocyte NADPH oxidase (phox) complex. They are found in proteins involved in vesicular trafficking, protein sorting, and lipid modification. It was recently reported that certain PX domains specifically recognize phosphatidylinositol 3-phosphate (PtdIns-3-P) and drive recruitment of their host proteins to the cytoplasmic leaflet of endosomal and/or vacuolar membranes where this phosphoinositide is enriched. We have analyzed phosphoinositide binding by all 15 PX domains encoded by the Saccharomyces cerevisiae genome. All yeast PX domains specifically recognize PtdIns-3-P in protein-lipid overlay experiments, with just one exception (a significant sequence outlier). In surface plasmon resonance studies, four of the yeast PX domains bind PtdIns-3-P with high (micromolar range) affinity. Although the remaining PX domains specifically recognize PtdIns-3-P, they bind this lipid with only low affinity. Interestingly, many proteins with "low affinity" PX domains are known to form large multimeric complexes, which may increase the overall avidity for membranes. Our results establish that PtdIns-3-P, and not other phosphoinositides, is the target of all PX domains in S. cerevisiae and suggest a role for PX domains in assembly of multiprotein complexes at specific membrane surfaces.

Amino Acid Sequence↗
PubMed1995

Molecular characterization of a lipid-modified virulence-associated protein of Rhodococcus equi and its potential in protective immunity.

Virulent strains of Rhodococcus equi produce plasmid-mediated 15- and 17-kDa proteins, which are thermoregulated and apparently surface-expressed. We demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) that R. equi produce three antigenically-related virulence-associated proteins, a diffuse 18-22-kDa, a 17.5-kDa and a 15-kDa protein. Phase partitioning of whole cells of R. equi strain 103 with Triton X-114 (TX-114) and labelling with [3H]-labelled palmitic acid showed that the two higher molecular weight proteins are hydrophobic and lipid modified. The 15-kDa protein did not partition into TX-114 and was not lipid modified. Cloning and expression of a fragment of the R. equi virulence plasmid in Escherichia coli showed that the three proteins were expressed from a single gene. Sequence analysis of this gene (designated vapA) revealed a 570-bp open reading frame encoding a polypeptide of 189 amino acids with a calculated molecular mass of 19,175 Da. The mature, nonlipid modified protein had a calculated mass of 16,246 Da. The 17.5- and 18-22-kDa forms of the protein are therefore due to lipid modification. No significant sequence homology of the vapA gene with other reported nucleotide sequences were found. Opsonization of virulent R. equi with an IgG1 mouse monoclonal antibody (MAb103) to the VapA protein significantly enhanced uptake in the murine macrophage cell line IC-21. Intraperitoneal injection of mice with Mab103 enhanced initial clearance from the liver of mice challenged intravenously with R. equi. Immunization of mice with the lipid-modified VapA purified by SDS-PAGE fractionation or with acetone precipitated VapA protein following TX-114 extraction resulted in significantly enhanced clearance from the liver and spleen following intravenous challenge. The VapA protein of R. equi appears therefore to be a protective immunogen.

Actinomycetales Infections↗
PubMed2004

Coupling actin and membrane dynamics during calcium-regulated exocytosis: a role for Rho and ARF GTPases.

Release of neurotransmitters and hormones occurs by calcium-regulated exocytosis, a process that shares many similarities in neurons and neuroendocrine cells. Exocytosis is confined to specific regions in the plasma membrane, where actin remodelling, lipid modifications and protein-protein interactions take place to mediate vesicle/granule docking, priming and fusion. The spatial and temporal coordination of the various players to form a "fast and furious" machinery for secretion remain poorly understood. ARF and Rho GTPases play a central role in coupling actin dynamics to membrane trafficking events in eukaryotic cells. Here, we review the role of Rho and ARF GTPases in supplying actin and lipid structures required for synaptic vesicle and secretory granule exocytosis. Their possible functional interplay may provide the molecular cues for efficient and localized exocytotic fusion.

ADP-Ribosylation Factors↗
PubMed1982

Effect of dietary fat saturation, cholesterol and cholestyramine on acyl-CoA: cholesterol acyltransferase activity in rabbit intestinal microsomes.

The regulation of intestinal acyl-CoA: cholesterol acyltransferase was investigated by dietary manipulation. Rabbits were fed the following diets: normal rabbit chow, 10% safflower oil, safflower oil plus 1% cholesterol, coconut oil plus 1% cholesterol, or cholestyramine. Acyl-CoA: cholesterol acyltransferase activity was increased in intestinal microsomes from animals fed safflower oil but not from animals fed coconut oil. Both diets containing cholesterol increased acyl-CoA: cholesterol acyltransferase activity; however, the safflower oil plus cholesterol diet was a more potent stimulator than coconut oil plus cholesterol. Cholestyramine decreased microsomal acyl-CoA: cholesterol acyltransferase activity. The different diets significantly modified microsomal lipid content in these groups. The two cholesterol diets resulted in equal increments in microsomal cholesterol. Microsomal cholesterol was unchanged in animals on the safflower oil diet; however, coconut oil and cholestyramine decreased the cholesterol content. Linoleic acid content increased in microsomes from animals on both the safflower oil-containing diets. Myristic acid accumulated and linoleic acid was decreased in microsomes from animals on both diets containing coconut oil. Subcellular fractionation of the intestine yielded a 4-fold enhancement of acyl-CoA: cholesterol acyltransferase activity in the rough endoplasmic reticulum. The lipid modifications and the subsequent changes in acyl-CoA: cholesterol acyltransferase activity in the rough endoplasmic reticulum from animals on normal, safflower oil, and safflower oil plus cholesterol diets paralleled that observed in the crude microsomal preparations. The changes in acyl-CoA: cholesterol acyltransferase activity observed with the different diets were not due to changes in microsomal fatty acyl-CoA pool size. It is concluded that dietary manipulation can alter microsomal lipid content. Microsomal fat saturation, independent of microsomal cholesterol content, regulates intestinal acyl-CoA: cholesterol acyltransferase and modifies the stimulatory effect of exogenous cholesterol on this enzyme.

Acyltransferases↗
PubMed1989

pCloDF13-encoded bacteriocin release proteins with shortened carboxyl-terminal segments are lipid modified and processed and function in release of cloacin DF13 and apparent host cell lysis.

By oligonucleotide-directed mutagenesis, stop codon mutations were introduced at various sites in the pCloDF13-derived bacteriocin release protein (BRP) structural gene. The expression, lipid modification (incorporation of [3H]palmitate), and processing (in the presence and absence of globomycin) of the various carboxyl-terminal shortened BRPs were analyzed by a special electrophoresis system and immunoblotting with an antiserum raised against a synthetic BRP peptide, and their functioning with respect to release of cloacin DF13, lethality, and apparent host cell lysis were studied in Sup-, supF, and supP strains of Escherichia coli. All mutant BRPs were stably expressed, lipid modified, and processed by signal peptidase II, albeit with different efficiencies. The BRP signal peptide appeared to be extremely stable and accumulated in induced cells. Full induction of the mutant BRPs, including the shortest containing only 4 amino acid residues of the mature polypeptide, resulted in phospholipase A-dependent and Mg2+-suppressible apparent cell lysis. The extent of this lysis varied with the mutant BRP used. Induction of all mutant BRPs also prevented colony formation, which appeared to be phospholipase A independent. One shortened BRP, containing 20 amino acid residues of the mature polypeptide, was still able to bring about the release of cloacin DF13. The results indicated that the 8-amino-acid carboxyl-terminal segment of the BRP contains a strong antigenic determinant and that a small segment between amino acid residues 17 and 21, located in the carboxyl-terminal half of the BRP, is important for release of cloacin DF13. Either the stable signal peptide or the acylated amino-terminal BRP fragments (or both) are involved in host cell lysis and lethality.

Acylation↗
PubMed2002

Peering inside lipid rafts and caveolae.

Clustering of proteins into membrane microdomains, such as lipid rafts and caveolae, could act as a mechanism for regulating cell signaling and other cellular functions. Certain lipid modifications are hypothesized to target proteins to these domains on the cytoplasmic leaflet of the plasma membrane. This concept has now been tested in living cells using an assay sensitive to the lateral distribution of proteins in membranes over sub-micron distances.

Animals↗
PubMed2004

Dietary lipids modify the age-associated changes in intestinal uptake of fructose in rats.

Because reduced nutrient absorption may contribute to malnourishment in the elderly, age and diet modulate fructose uptake in mice, and alterations in fructose uptake may be paralleled by changes in the abundance of fructose transporters, the objectives of this study were to determine 1) the effects of aging on fructose absorption in rats, 2) the effect of feeding diets enriched with saturated fatty acids (SFA) vs. polyunsaturated fatty acids (PUFA), and 3) the mechanisms of these age-and diet-associated changes. Male Fischer 344 rats aged 1, 9, and 24 mo received isocaloric diets enriched with SFA or PUFA. The uptake of (14)C-labeled D-fructose was determined in vitro using the intestinal sheet method. Northern and Western blot analyses and immunohistochemistry were used to determine the abundance of sodium-independent glucose and fructose transporters (GLUT)2 and GLUT5. When expressed on the basis of mucosal surface area, jejunal fructose uptake was increased in 9 and 24 mo compared with 1-mo-old animals fed SFA. PUFA-fed animals demonstrated increased fructose uptake at 24 mo compared with younger animals. Ileal fructose uptake was increased with SFA vs. PUFA in 9-mo-old rats but was reduced with SFA in 1- and 24-mo-old rats. Variations in GLUT2 and GLUT5 abundance did not parallel changes in uptake. These results indicate that 1) age increases fructose uptake when expressed on the basis of mucosal surface area, 2) age influences the adaptive response to dietary lipid modifications, and 3) alterations in fructose uptake are not explained by variations in GLUT2 or GLUT5.

Absorption↗
PubMed2004

Identification of a novel domain of Ras and Rap1 that directs their differential subcellular localizations.

The small GTPase Ha-Ras and Rap1A exhibit high mutual sequence homology and share various target proteins. However, they exert distinct biological functions and exhibit differential subcellular localizations; Rap1A is predominantly localized in the perinuclear region including the Golgi apparatus and endosomes, whereas Ha-Ras is predominantly localized in the plasma membrane. Here, we have identified a small region in Rap1A that is crucial for its perinuclear localization. Analysis of a series of Ha-Ras-Rap1A chimeras shows that Ha-Ras carrying a replacement of amino acids 46-101 with that of Rap1 exhibits the perinuclear localization. Subsequent mutational studies indicate that Rap1A-type substitutions within five amino acids at positions 85-89 of Ha-Ras, such as NNTKS85-89TAQST, NN85-86TA, and TKS87-89QST, are sufficient to induce the perinuclear localization of Ha-Ras. In contrast, substitutions of residues surrounding this region, such as FAI82-84YSI and FEDI90-93FNDL, have no effect on the plasma membrane localization of Ha-Ras. A chimeric construct consisting of amino acids 1-134 of Rap1A and 134-189 of Ha-Ras, which harbors both the palmitoylation and farnesylation sites of Ha-Ras, exhibits the perinuclear localization like Rap1A. Introduction of a Ha-Ras-type substitution into amino acids 85-89 (TAQST85-89NNTKS) of this chimeric construct causes alteration of its predominant subcellular localization site from the perinuclear region to the plasma membrane. These results indicate that a previously uncharacterized domain spanning amino acids 85-89 of Rap1A plays a pivotal role in its perinuclear localization. Moreover, this domain acts dominantly over COOH-terminal lipid modification of Ha-Ras, which has been considered to be essential and sufficient for the plasma membrane localization.

Amino Acid Sequence↗
PubMed1990

Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH)

BACKGROUND AND METHODS: The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. RESULTS: When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction. CONCLUSIONS: Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.

Adult↗
PubMed2004

Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids.

The Shh protein contains both N-terminal and C-terminal lipids. The functional redundancy of these lipid moieties is presently unclear. Here, we compare the relative roles of the N- and C-terminal lipids in early rat striatal neuronal differentiation, membrane association and multimerization, and ventralizing activity in the zebrafish forebrain. We show that these lipid act synergistically in cell tethering and the formation of a large (L) multimer (669 kDa). However, the C-terminal lipid antagonizes the rat striatal neuronal differentiation-inducing activity of the N-terminal lipid. In addition, multimerization is required but not sufficient for the differentiation-inducing activity. Based on the presence of different N- and C-lipid-containing Shh proteins in the rat embryo, and on their different activities, we propose that both N- and C-terminal lipids are required for the formation of multimers involved in long-range signaling, and that the C-terminal lipid may function in long-range signaling by reducing Shh activity until it reaches its long-range target. Comparative analysis of the ventralizing activities of different N- and C-terminal lipid-containing Shh proteins in the zebrafish forebrain shows that the presence of at least one lipid is required for signaling activity, suggesting that lipid modification of Shh is a conserved requirement for signaling in the forebrain of rodents and zebrafish.

Animals↗
PubMed1996

Protein prenylation: molecular mechanisms and functional consequences.

Prenylation is a class of lipid modification involving covalent addition of either farnesyl (15-carbon) or geranylgeranyl (20-carbon) isoprenoids to conserved cysteine residues at or near the C-terminus of proteins. Known prenylated proteins include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins (G proteins), the subunits of trimeric G proteins, protein kinases, and at least one viral protein. Prenylation promotes membrane interactions of most of these proteins, which is not surprising given the hydrophobicity of the lipids involved. In addition, however, prenylation appears to play a major role in several protein-protein interactions involving these species. The emphasis in this review is on the enzymology of prenyl protein processing and the functional significance of prenylation in cellular events. Several other recent reviews provide more detailed coverage of aspects of prenylation that receive limited attention here owing to length restrictions (1-4).

GTP-Binding Proteins↗