The Experts below are selected from a list of 246 Experts worldwide ranked by ideXlab platform
David E Cohen - One of the best experts on this subject based on the ideXlab platform.
-
Phosphatidylcholine transfer protein stard2 promotes microvesicular steatosis and liver injury in murine experimental steatohepatitis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2017Co-Authors: Hayley T Nicholls, Jason L Hornick, David E CohenAbstract:Phosphatidylcholine transport protein (PC-TP) is a highly specific Phosphatidylcholine-binding protein that we previously showed to regulate hepatocellular nutrient metabolism through its interacti...
-
interacting proteins dictate function of the minimal start domain Phosphatidylcholine transfer protein stard2
Journal of Biological Chemistry, 2007Co-Authors: Keishi Kanno, Diana S Agate, Brandon J Fanelli, Neil Wagle, Erez F Scapa, Chinweike Ukomadu, David E CohenAbstract:The Star (steroidogenic acute regulatory protein)-related transfer (START) domain superfamily is characterized by a distinctive lipid-binding motif. START domains typically reside in multidomain proteins, suggesting their function as lipid sensors that trigger biological activities. Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is an example of a START domain minimal protein that consists only of the lipid-binding motif. PC-TP, which binds Phosphatidylcholine exclusively, is expressed during embryonic development and in several tissues of the adult mouse, including liver. Although it catalyzes the intermembrane exchange of Phosphatidylcholines in vitro, this activity does not appear to explain the various metabolic alterations observed in mice lacking PC-TP. Here we demonstrate that PC-TP function may be mediated via interacting proteins. Yeast two-hybrid screening using libraries prepared from mouse liver and embryo identified Them2 (thioesterase superfamily member 2) and the homeodomain transcription factor Pax3 (paired box gene 3), respectively, as PC-TP-interacting proteins. These were notable because the START domain superfamily contains multidomain proteins in which the START domain coexists with thioesterase domains in mammals and with homeodomain transcription factors in plants. Interactions were verified in pulldown assays, and colocalization with PC-TP was confirmed within tissues and intracellularly. The acyl-CoA thioesterase activity of purified recombinant Them2 was markedly enhanced by recombinant PC-TP. In tissue culture, PC-TP coactivated the transcriptional activity of Pax3. These findings suggest that PC-TP functions as a Phosphatidylcholine-sensing molecule that engages in diverse regulatory activities that depend upon the cellular expression of distinct interacting proteins.
-
structure of human Phosphatidylcholine transfer protein in complex with its ligand
Nature Structural & Molecular Biology, 2002Co-Authors: Steven L Roderick, Diana S Agate, Wayne W Chan, Laurence R Olsen, Matt W Vetting, Kanagalaghatta R Rajashankar, David E CohenAbstract:Phosphatidylcholines (PtdChos) comprise the most common phospholipid class in eukaryotic cells. In mammalian cells, these insoluble molecules are transferred between membranes by a highly specific Phosphatidylcholine transfer protein (PC-TP) belonging to the steroidogenic acute regulatory protein related transfer (START) domain superfamily of hydrophobic ligand-binding proteins. The crystal structures of human PC-TP in complex with dilinoleoyl-PtdCho or palmitoyl-linoleoyl-PtdCho reveal that a single well-ordered PtdCho molecule occupies a centrally located tunnel. The positively charged choline headgroup of the lipid engages in cation–π interactions within a cage formed by the faces of three aromatic residues. These binding determinants and those for the phosphoryl group may be exposed to the lipid headgroup at the membrane–water interface by a conformational change involving the amphipathic C-terminal helix and an Ω-loop. The structures presented here provide a basis for rationalizing the specificity of PC-TP for PtdCho and may identify common features used by START proteins to bind their hydrophobic ligands.
Zbigniew A Figaszewski - One of the best experts on this subject based on the ideXlab platform.
-
the equilibria of Phosphatidylcholine fatty acid and Phosphatidylcholine amine in monolayers at the air water interface
Colloids and Surfaces B: Biointerfaces, 2011Co-Authors: Aneta D Petelska, Zbigniew A FigaszewskiAbstract:Monolayers of Phosphatidylcholine, fatty acid and amine and binary mixtures Phosphatidylcholine-fatty acid or Phosphatidylcholine-amine were investigated at the air/water interface. Phosphatidylcholine (lecithin, PC), stearic acid (SA), palmitic acid (PA), decanoic acid (DA) and decylamine (DE) were used to the experiment. The surface tension values of pure and mixed monolayers were used to calculate π-A isotherms. The surface tension measurements were carried out at 22°C using an improved Teflon trough and a Nima 9000 tensiometer. The Teflon trough was filled with a subphase of triple-distilled water. Known amounts of lipid dissolved in 1-chloropropane were placed at the surface using a syringe. The interactions between lecithin and fatty acid as well as Phosphatidylcholine and amine result in significant deviations from the additivity rule. An equilibrium theory to describe the behaviour of monolayer components at the air/water interface was developed in order to obtain the stability constants of PC-SA, PC-PA, PC-DA and PC-DE complexes. We considered the equilibrium between the individual components and the complex and established that lecithin and fatty acid as well as Phosphatidylcholine and amine formed highly stable 1:1 complexes.
-
interfacial tension of the lipid membrane formed from lipid fatty acid and lipid amine systems
Bioelectrochemistry, 2007Co-Authors: Aneta D Petelska, Monika Naumowicz, Zbigniew A FigaszewskiAbstract:Abstract Interfacial tension has been determined for Phosphatidylcholine–stearic acid and Phosphatidylcholine–stearylamine membranes. Phosphatidylcholine, stearic acid and stearylamine were used in the experimental. The interfacial tension values of the pure components are 1.62 × 10− 3 N/m, − 1.54 × 10− 2 N/m and 4.40 × 10− 3 N/m (hypothetical values), respectively. The 1:1 complexes were formed during formation of Phosphatidylcholine–stearic acid and Phosphatidylcholine–stearylamine membranes. The following parameters describing the complexes were determined: the surface concentrations of the lipid membranes formed from these complexes, A3− 1, the interfacial tensions of such membranes, γ3 and the stability constants of these complexes, K.
Ronald N Mcelhaney - One of the best experts on this subject based on the ideXlab platform.
-
the antimicrobial peptide gramicidin s permeabilizes phospholipid bilayer membranes without forming discrete ion channels
Biochimica et Biophysica Acta, 2008Co-Authors: Md Ashrafuzzaman, Olaf S Andersen, Ronald N McelhaneyAbstract:We examined the permeabilization of lipid bilayers by the β-sheet, cyclic antimicrobial decapeptide gramicidin S (GS) in phospholipid bilayers formed either by mixtures of zwitterionic diphytanoylPhosphatidylcholine and anionic diphytanoylphosphatidylglycerol or by single zwitterionic unsaturated Phosphatidylcholines having various hydrocarbon chain lengths, with and without cholesterol. In the zwitterionic bilayers formed by the Phosphatidylcholines, without or with cholesterol, the peptide concentrations and membrane potentials required to initiate membrane permeabilization vary little as function of bilayer thickness and cholesterol content. In all the systems tested, the GS-induced transient ion conductance events exhibit a broad range of conductances, which are little affected by the bilayer composition or thickness. In the zwitterionic Phosphatidylcholine bilayers, the effect of GS does not depend on the polarity of the transmembrane potential; however, in bilayers formed from mixtures of Phosphatidylcholines and anionic phospholipids, the polarity of the transmembrane potential becomes important, with the GS-induced conductance events being much more frequent when the GS-containing solution is positive relative to the GS-free solution. Overall, these results suggest that GS does not form discrete, well-defined, channel-like structures in phospholipid bilayers, but rather induces a wide variety of transient, differently sized defects which serve to compromise the bilayer barrier properties for small electrolytes.
-
differential scanning calorimetric study of the effect of cholesterol on the thermotropic phase behavior of a homologous series of linear saturated Phosphatidylcholines
Biochemistry, 1993Co-Authors: Todd P W Mcmullen, Ruthven N A H Lewis, Ronald N McelhaneyAbstract:: We have studied the effects of cholesterol on the thermotropic phase behavior of aqueous dispersions of a homologous series of linear saturated Phosphatidylcholines, using high-sensitivity differential scanning calorimetry and an experimental protocol which ensures that broad, low-enthalpy phase transitions are accurately monitored. We find that the incorporation of small amounts of cholesterol progressively decreases the temperature and the enthalpy, but not the cooperativity, of the pretransition of all Phosphatidylcholines exhibiting such a pretransition and that the pretransition is completely abolished at cholesterol concentrations above 5 mol % in all cases. The incorporation of increasing quantities of cholesterol also alters the main or chain-melting phase transition of these phospholipid bilayers in both hydrocarbon chain length-dependent and hydrocarbon chain length-independent ways. At cholesterol concentrations of from 1 to 20-25 mol %, the DSC endotherms of all Phosphatidylcholines studied consist of a superimposed sharp and broad component, the former ascribed to the melting of cholesterol-poor and the latter to the melting of the cholesterol-rich Phosphatidylcholine domains. The temperature and cooperativity of the sharp component are reduced only slightly and in a chain length-independent manner with increasing cholesterol concentration, an effect we ascribe to the colligative effect of the presence of small quantities of cholesterol at the domain boundaries. Moreover, the enthalpy of the sharp component decreases and becomes zero at 20-25 mol % cholesterol for all of the Phosphatidylcholines examined.(ABSTRACT TRUNCATED AT 250 WORDS)
Alicia Alonso - One of the best experts on this subject based on the ideXlab platform.
-
mixing brain cerebrosides with brain ceramides cholesterol and phospholipids
Scientific Reports, 2019Co-Authors: Emilio J Gonzalezramirez, Felix M Goni, Alicia AlonsoAbstract:The properties of bilayers composed of pure brain cerebroside (bCrb) or of binary mixtures of bCrb with brain ceramide, cholesterol, egg Phosphatidylcholine or brain sphingomyelin have been studied using a combination of physical techniques. Pure bCrb exhibits a rather narrow gel-fluid transition centred at ≈65 °C, with a half-width at half-height T1/2 ≈ 3 °C. bCrb mixes well with both fluid and gel phospholipids and ceramide, and it rigidifies bilayers of egg Phosphatidylcholine or brain sphingomyelin when the latter are in the fluid state. Cholesterol markedly widens the bCrb gel-fluid transition, while decreasing the associated transition enthalpy, in the manner of cholesterol mixtures with saturated Phosphatidylcholines, or sphingomyelins. Laurdan and DPH fluorescence indicate the formation of fluid ordered phases in the bCrb:cholesterol mixtures. Macroscopic phase separation of more and less fluid domains is observed in giant unilamellar vesicles consisting of bCrb:egg Phosphatidylcholine or bCrb:sphingomyelin. Crb capacity to induce bilayer permeabilization or transbilayer (flip-flop) lipid motion is much lower than those of ceramides. The mixtures explored here contained mostly bCrb concentrations >50 mol%, mimicking the situation of cell membranes in Gaucher’s disease, or of the Crb-enriched microdomains proposed to exist in healthy cell plasma membranes.
Dennis E. Vance - One of the best experts on this subject based on the ideXlab platform.
-
Phosphatidylcholine and choline homeostasis
Journal of lipid research, 2008Co-Authors: Dennis E. VanceAbstract:Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) alpha die during embryogenesis, whereas mice that lack CKbeta unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) alpha also die during early embryogenesis, whereas mice that lack CTbeta exhibit gonadal dysfunction. The cytidylyltransferase beta isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die from steatohepatitis and liver failure when placed on a choline-deficient diet. Hence, choline is an essential nutrient. PC biosynthesis is required for normal very low density lipoprotein secretion from hepatocytes. Recent studies indicate that choline is recycled in the liver and redistributed from kidney, lung, and intestine to liver and brain when choline supply is attenuated.
-
biochemical and evolutionary significance of phospholipid methylation
Journal of Biological Chemistry, 1998Co-Authors: Christopher J. Walkey, Liqing Yu, Luis B Agellon, Dennis E. VanceAbstract:Abstract All nucleated mammalian cells synthesize Phosphatidylcholine from choline via the CDP-choline pathway. Hepatocytes have a second pathway for the synthesis of Phosphatidylcholine, a stepwise methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamineN-methyltransferase and encoded by the Pemptgene. We report that when Pempt-deficient mice were fed a choline-deficient diet for 3 days, severe liver pathology occurred apparently due to a lack of Phosphatidylcholine biosynthesis. The hepatic concentration of Phosphatidylcholine decreased by 50% compared with wild type mice on the diet. The levels of plasma triacylglycerols and cholesterol were decreased by greater than 90% in thePempt-deficient mice. We suggest that the Pemptgene has been maintained during evolution to provide Phosphatidylcholine when dietary choline is insufficient, as might occur during starvation or pregnancy.
