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Results: 1 to 10 of 72

Publication Record


Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its α-Helical Conformation, and Inhibits γ-Secretase Nonselectively in Liposomes.
Kamp F, Scheidt HA, Winkler E, Basset G, Heinel H, Hutchison JM, LaPointe LM, Sanders CR, Steiner H, Huster D
(2018) ACS Chem Neurosci 9: 1702-1713
MeSH Terms: Amyloid Precursor Protein Secretases, Amyloid beta-Protein Precursor, Bexarotene, Cholesterol, HEK293 Cells, Humans, Liposomes, Molecular Structure, Neuroprotective Agents, Phosphatidylcholines, Protein Conformation, alpha-Helical, Protein Domains, Receptor, Notch1, Static Electricity
Show Abstract · Added November 21, 2018
Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-β (Aβ)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Aβ clearance mechanism. However, whether bexarotene induces removal of Aβ plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain α-helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by γ-secretase of the APP C-terminal fragment C99 to release Aβ in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major γ-secretase substrate, demonstrating that its inhibition of γ-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Aβ metabolism through multiple mechanisms.
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14 MeSH Terms
Evaluation of Collision Cross Section Calibrants for Structural Analysis of Lipids by Traveling Wave Ion Mobility-Mass Spectrometry.
Hines KM, May JC, McLean JA, Xu L
(2016) Anal Chem 88: 7329-36
MeSH Terms: Calibration, Ions, Nitrogen, Peptides, Phosphatidylcholines, Phosphatidylethanolamines, Spectrometry, Mass, Electrospray Ionization
Show Abstract · Added December 17, 2018
Collision cross section (CCS) measurement of lipids using traveling wave ion mobility-mass spectrometry (TWIM-MS) is of high interest to the lipidomics field. However, currently available calibrants for CCS measurement using TWIM are predominantly peptides that display quite different physical properties and gas-phase conformations from lipids, which could lead to large CCS calibration errors for lipids. Here we report the direct CCS measurement of a series of phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs) in nitrogen using a drift tube ion mobility (DTIM) instrument and an evaluation of the accuracy and reproducibility of PCs and PEs as CCS calibrants for phospholipids against different classes of calibrants, including polyalanine (PolyAla), tetraalkylammonium salts (TAA), and hexakis(fluoroalkoxy)phosphazines (HFAP), in both positive and negative modes in TWIM-MS analysis. We demonstrate that structurally mismatched calibrants lead to larger errors in calibrated CCS values while the structurally matched calibrants, PCs and PEs, gave highly accurate and reproducible CCS values at different traveling wave parameters. Using the lipid calibrants, the majority of the CCS values of several classes of phospholipids measured by TWIM are within 2% error of the CCS values measured by DTIM. The development of phospholipid CCS calibrants will enable high-accuracy structural studies of lipids and add an additional level of validation in the assignment of identifications in untargeted lipidomics experiments.
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MeSH Terms
TLR3 Agonist Poly-IC Induces IL-33 and Promotes Myelin Repair.
Natarajan C, Yao SY, Sriram S
(2016) PLoS One 11: e0152163
MeSH Terms: Animals, Cell Differentiation, Cell Nucleus, Cell Polarity, Cells, Cultured, Corpus Callosum, Enzyme Activation, Intercellular Signaling Peptides and Proteins, Interleukin-33, Lysophosphatidylcholines, Macrophages, Models, Biological, Myelin Basic Protein, Myelin Sheath, Neuroglia, Oligodendroglia, Phenotype, Phosphorylation, Poly I-C, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Recombinant Proteins, Stem Cells, Toll-Like Receptor 3, Transcription, Genetic, Up-Regulation, Wound Healing, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added April 18, 2017
BACKGROUND - Impaired remyelination of demyelinated axons is a major cause of neurological disability. In inflammatory demyelinating disease of the central nervous system (CNS), although remyelination does happen, it is often incomplete, resulting in poor clinical recovery. Poly-IC a known TLR3 agonist and IL-33, a cytokine which is induced by poly-IC are known to influence recovery and promote repair in experimental models of CNS demyelination.
METHODOLOGY AND PRINCIPAL FINDINGS - We examined the effect of addition of poly-IC and IL-33 on the differentiation and maturation of oligodendrocyte precursor cells (OPC) cultured in vitro. Both Poly-IC and IL-33 induced transcription of myelin genes and the differentiation of OPC to mature myelin forming cells. Poly-IC induced IL-33 in OPC and addition of IL-33 to in vitro cultures, amplified further, IL-33 expression suggesting an autocrine regulation of IL-33. Poly-IC and IL-33 also induced phosphorylation of p38MAPK, a signaling molecule involved in myelination. Following the induction of gliotoxic injury with lysolecithin to the corpus callosum (CC), treatment of animals with poly-IC resulted in greater recruitment of OPC and increased staining for myelin in areas of demyelination. Also, poly-IC treated animals showed greater expression of IL-33 and higher expression of M2 phenotype macrophages in the CC.
CONCLUSION/SIGNIFICANCE - Our studies suggest that poly-IC and IL-33 play a role in myelin repair by enhancing expression of myelin genes and are therefore attractive therapeutic agents for use as remyelinating agents in human demyelinating disease.
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28 MeSH Terms
Topologically Diverse Human Membrane Proteins Partition to Liquid-Disordered Domains in Phase-Separated Lipid Vesicles.
Schlebach JP, Barrett PJ, Day CA, Kim JH, Kenworthy AK, Sanders CR
(2016) Biochemistry 55: 985-8
MeSH Terms: Amyloid beta-Protein Precursor, Caveolin 3, Cholesterol, Fluorescent Dyes, Humans, Hydrophobic and Hydrophilic Interactions, Membrane Microdomains, Microscopy, Confocal, Microscopy, Fluorescence, Models, Molecular, Myelin Proteins, Peptide Fragments, Phosphatidylcholines, Phosphatidylethanolamines, Protein Conformation, Protein Interaction Domains and Motifs, Recombinant Proteins, Rhodamines, Sphingomyelins, Unilamellar Liposomes
Show Abstract · Added February 12, 2016
The integration of membrane proteins into "lipid raft" membrane domains influences many biochemical processes. The intrinsic structural properties of membrane proteins are thought to mediate their partitioning between membrane domains. However, whether membrane topology influences the targeting of proteins to rafts remains unclear. To address this question, we examined the domain preference of three putative raft-associated membrane proteins with widely different topologies: human caveolin-3, C99 (the 99 residue C-terminal domain of the amyloid precursor protein), and peripheral myelin protein 22. We find that each of these proteins are excluded from the ordered domains of giant unilamellar vesicles containing coexisting liquid-ordered and liquid-disordered phases. Thus, the intrinsic structural properties of these three topologically distinct disease-linked proteins are insufficient to confer affinity for synthetic raft-like domains.
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20 MeSH Terms
Apolipoprotein A-V is present in bile and its secretion increases with lipid absorption in Sprague-Dawley rats.
Zhang LS, Sato H, Yang Q, Ryan RO, Wang DQ, Howles PN, Tso P
(2015) Am J Physiol Gastrointest Liver Physiol 309: G918-25
MeSH Terms: Animals, Apolipoprotein A-V, Apolipoproteins, Bile, Biliary Fistula, Chylomicrons, Disease Models, Animal, Duodenum, Emulsions, Fasting, Intestinal Absorption, Liver, Lymph, Male, Phosphatidylcholines, Phospholipids, Rats, Sprague-Dawley, Soybean Oil, Taurocholic Acid, Time Factors, Up-Regulation
Show Abstract · Added December 8, 2015
Apolipoprotein (apo) A-V is a protein synthesized only in the liver that dramatically modulates plasma triglyceride levels. Recent studies suggest a novel role for hepatic apoA-V in regulating the absorption of dietary triglycerides, but its mode of action on the gut remains unknown. The aim of this study was to test for apoA-V in bile and to determine whether its secretion is regulated by dietary lipids. After an overnight recovery, adult male Sprague-Dawley bile fistula rats indeed secreted apoA-V into bile at a constant rate under fasting conditions. An intraduodenal bolus of intralipid (n = 12) increased the biliary secretion of apoA-V but not of other apolipoproteins, such as A-I, A-IV, B, and E. The lipid-induced increase of biliary apoA-V was abolished under conditions of poor lymphatic lipid transport, suggesting that the stimulation is regulated by the magnitude of lipids associated with chylomicrons transported into lymph. We also studied the secretion of apoA-V into bile immediately following bile duct cannulation. Biliary apoA-V increased over time (∼6-fold increase at hour 16, n = 8) but the secretions of other apolipoproteins remained constant. Replenishing luminal phosphatidylcholine and taurocholate (n = 9) only enhanced apoA-V secretion in bile, suggesting that the increase was not due to depletion of phospholipids or bile salts. This is the first study to demonstrate that apoA-V is secreted into bile, introducing a potential route of delivery of hepatic apoA-V to the gut lumen. Our study also reveals the uniqueness of apoA-V secretion into bile that is regulated by mechanisms different from other apolipoproteins.
Copyright © 2015 the American Physiological Society.
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21 MeSH Terms
Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma.
Murph MM, Jiang GW, Altman MK, Jia W, Nguyen DT, Fambrough JM, Hardman WJ, Nguyen HT, Tran SK, Alshamrani AA, Madan D, Zhang J, Prestwich GD
(2015) Bioorg Med Chem 23: 5999-6013
MeSH Terms: Cell Line, Tumor, Humans, Lysophosphatidylcholines, Melanoma, Neovascularization, Pathologic, Sulfones
Show Abstract · Added September 20, 2016
Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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6 MeSH Terms
Notch Transmembrane Domain: Secondary Structure and Topology.
Deatherage CL, Lu Z, Kim JH, Sanders CR
(2015) Biochemistry 54: 3565-8
MeSH Terms: Humans, Lipid Bilayers, Lysophosphatidylcholines, Models, Molecular, Nuclear Magnetic Resonance, Biomolecular, Peptide Fragments, Phosphatidylcholines, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Receptor, Notch1, Recombinant Proteins, Surface Properties
Show Abstract · Added February 5, 2016
The Notch signaling pathway is critical in development, neuronal maintenance, and hematopoiesis. An obligate step in the activation of this pathway is cleavage of its transmembrane (TM) domain by γ-secretase. While the soluble domains have been extensively studied, little has been done to characterize its TM and flanking juxtamembrane (JM) segments. Here, we present the results of nuclear magnetic resonance (NMR) studies of the human Notch1 TM/JM domain. The TM domain is largely α-helical. While the flanking JM segments do not adopt regular secondary structure, they interact with the membrane surface, suggesting membrane interactions may play a role in modulating its cleavage by γ-secretase and subsequent NOTCH signaling function.
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13 MeSH Terms
Structural investigation of the transmembrane domain of KCNE1 in proteoliposomes.
Sahu ID, Kroncke BM, Zhang R, Dunagan MM, Smith HJ, Craig A, McCarrick RM, Sanders CR, Lorigan GA
(2014) Biochemistry 53: 6392-401
MeSH Terms: Amino Acid Substitution, Humans, Lipid Bilayers, Liposomes, Molecular Dynamics Simulation, Phosphatidylcholines, Phosphatidylglycerols, Potassium Channels, Voltage-Gated, Protein Structure, Secondary, Protein Structure, Tertiary, Thermodynamics
Show Abstract · Added November 21, 2018
KCNE1 is a single-transmembrane protein of the KCNE family that modulates the function of voltage-gated potassium channels, including KCNQ1. Hereditary mutations in KCNE1 have been linked to diseases such as long QT syndrome (LQTS), atrial fibrillation, sudden infant death syndrome, and deafness. The transmembrane domain (TMD) of KCNE1 plays a key role in mediating the physical association with KCNQ1 and in subsequent modulation of channel gating kinetics and conductance. However, the mechanisms associated with these roles for the TMD remain poorly understood, highlighting a need for experimental structural studies. A previous solution NMR study of KCNE1 in LMPG micelles revealed a curved transmembrane domain, a structural feature proposed to be critical to KCNE1 function. However, this curvature potentially reflects an artifact of working in detergent micelles. Double electron electron resonance (DEER) measurements were conducted on KCNE1 in LMPG micelles, POPC/POPG proteoliposomes, and POPC/POPG lipodisq nanoparticles to directly compare the structure of the TMD in a variety of different membrane environments. Experimentally derived DEER distances coupled with simulated annealing molecular dynamic simulations were used to probe the bilayer structure of the TMD of KCNE1. The results indicate that the structure is helical in proteoliposomes and is slightly curved, which is consistent with the previously determined solution NMR structure in micelles. The evident resilience of the curvature in the KCNE1 TMD leads us to hypothesize that the curvature is likely to be maintained upon binding of the protein to the KCNQ1 channel.
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MeSH Terms
High-resolution structures and orientations of antimicrobial peptides piscidin 1 and piscidin 3 in fluid bilayers reveal tilting, kinking, and bilayer immersion.
Perrin BS, Tian Y, Fu R, Grant CV, Chekmenev EY, Wieczorek WE, Dao AE, Hayden RM, Burzynski CM, Venable RM, Sharma M, Opella SJ, Pastor RW, Cotten ML
(2014) J Am Chem Soc 136: 3491-504
MeSH Terms: Antimicrobial Cationic Peptides, Fish Proteins, Hydrophobic and Hydrophilic Interactions, Immersion, Lipid Bilayers, Liquid Crystals, Molecular Dynamics Simulation, Phosphatidylcholines, Phosphatidylglycerols, Protein Structure, Secondary
Show Abstract · Added March 5, 2014
While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of (1)H-(15)N dipolar couplings and (15)N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (~25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ~1.2-3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.
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10 MeSH Terms
A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use.
Liu S, Brown JD, Stanya KJ, Homan E, Leidl M, Inouye K, Bhargava P, Gangl MR, Dai L, Hatano B, Hotamisligil GS, Saghatelian A, Plutzky J, Lee CH
(2013) Nature 502: 550-4
MeSH Terms: Acetyl-CoA Carboxylase, Animals, Circadian Rhythm, Diabetes Mellitus, Fatty Acids, Gene Expression Regulation, Homeostasis, Lipids, Lipogenesis, Liver, Male, Mice, Mice, Inbred C57BL, Muscles, Obesity, PPAR delta, Phosphatidylcholines, Principal Component Analysis
Show Abstract · Added September 6, 2016
Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/β and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.
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18 MeSH Terms