scholarly journals The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

2018 ◽  
Author(s):  
Harald F. Hofbauer ◽  
Michael Gecht ◽  
Sabine C. Fischer ◽  
Anja Seybert ◽  
Achilleas S. Frangakis ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Acyl Chain ◽  
Md Simulations ◽  
Membrane Biogenesis ◽  
Hydrophobic Core ◽  
Amphipathic Helix ◽  
The Family ◽  
Chain Composition ◽  
New Feature ◽  
Membrane Recognition

AbstractA key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important lipid intermediate and signaling lipid at the branch point of these pathways and constantly monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. Here, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for the selective binding to membranes containing PA over phosphatidylserine (PS). The insertion of the AH into the hydrophobic core of the membrane renders Opi1 sensitive to the lipid acyl chain composition as an important factor contributing to the regulation of membrane biogenesis. Based on these findings, we rationally designed the membrane binding properties of Opi1 to control its responsiveness in the physiological context. Using extensive molecular dynamics (MD) simulations, we identified two PA-selective three-finger grips that tightly bind the phosphate headgroup, while interacting less intimately and more transiently with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

scholarly journals The molecular recognition of phosphatidic acid by an amphipathic helix in Opi1

2018 ◽  
Vol 217 (9) ◽  
pp. 3109-3126 ◽  
Author(s):  
Harald F. Hofbauer ◽  
Michael Gecht ◽  
Sabine C. Fischer ◽  
Anja Seybert ◽  
Achilleas S. Frangakis ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Rational Design ◽  
Acyl Chain ◽  
Membrane Biogenesis ◽  
Amphipathic Helix ◽  
New Feature ◽  
Dynamics Simulations ◽  
Membrane Recognition ◽  
And Control

A key event in cellular physiology is the decision between membrane biogenesis and fat storage. Phosphatidic acid (PA) is an important intermediate at the branch point of these pathways and is continuously monitored by the transcriptional repressor Opi1 to orchestrate lipid metabolism. In this study, we report on the mechanism of membrane recognition by Opi1 and identify an amphipathic helix (AH) for selective binding of PA over phosphatidylserine (PS). The insertion of the AH into the membrane core renders Opi1 sensitive to the lipid acyl chain composition and provides a means to adjust membrane biogenesis. By rational design of the AH, we tune the membrane-binding properties of Opi1 and control its responsiveness in vivo. Using extensive molecular dynamics simulations, we identify two PA-selective three-finger grips that tightly bind the PA phosphate headgroup while interacting less intimately with PS. This work establishes lipid headgroup selectivity as a new feature in the family of AH-containing membrane property sensors.

scholarly journals The Profound Influence of Lipid Composition on the Catalysis of the Drug Target NADH Type II Oxidoreductase

Membranes ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 363
Author(s):  
Albert Godoy-Hernandez ◽  
Duncan G. G. McMillan
Keyword(s):  
Acyl Chain ◽  
Cellular Respiration ◽  
Type Ii ◽  
Nadh:Quinone Oxidoreductase ◽  
Chain Composition ◽  
Membrane Bound ◽  
Lipid Environment ◽  
Lipid Specificity ◽  
Mediated Catalysis ◽  
Quinone Pool

Lipids play a pivotal role in cellular respiration, providing the natural environment in which an oxidoreductase interacts with the quinone pool. To date, it is generally accepted that negatively charged lipids play a major role in the activity of quinone oxidoreductases. By changing lipid compositions when assaying a type II NADH:quinone oxidoreductase, we demonstrate that phosphatidylethanolamine has an essential role in substrate binding and catalysis. We also reveal the importance of acyl chain composition, specifically c14:0, on membrane-bound quinone-mediated catalysis. This demonstrates that oxidoreductase lipid specificity is more diverse than originally thought and that the lipid environment plays an important role in the physiological catalysis of membrane-bound oxidoreductases.

scholarly journals Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sheena Dass ◽  
Serena Shunmugam ◽  
Laurence Berry ◽  
Christophe-Sebastien Arnold ◽  
Nicholas J. Katris ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Phosphatidic Acid ◽  
De Novo ◽  
Lipid Synthesis ◽  
Parasite Development ◽  
Membrane Biogenesis ◽  
Membrane Phospholipids ◽  
Phosphatidic Acid Phosphatase ◽  
Intracellular Parasites ◽  
Parasite Survival

AbstractApicomplexa are obligate intracellular parasites responsible for major human diseases. Their intracellular survival relies on intense lipid synthesis, which fuels membrane biogenesis. Parasite lipids are generated as an essential combination of fatty acids scavenged from the host and de novo synthesized within the parasite apicoplast. The molecular and metabolic mechanisms allowing regulation and channeling of these fatty acid fluxes for intracellular parasite survival are currently unknown. Here, we identify an essential phosphatidic acid phosphatase in Toxoplasma gondii, TgLIPIN, as the central metabolic nexus responsible for controlled lipid synthesis sustaining parasite development. Lipidomics reveal that TgLIPIN controls the synthesis of diacylglycerol and levels of phosphatidic acid that regulates the fine balance of lipids between storage and membrane biogenesis. Using fluxomic approaches, we uncover the first parasite host-scavenged lipidome and show that TgLIPIN prevents parasite death by ‘lipotoxicity’ through effective channeling of host-scavenged fatty acids to storage triacylglycerols and membrane phospholipids.

scholarly journals Structural Characterization of Natural Yeast Phosphatidylcholine and Bacterial Phosphatidylglycerol Lipid Multilayers by Neutron Diffraction

2021 ◽  
Vol 9 ◽  
Author(s):  
Alessandra Luchini ◽  
Giacomo Corucci ◽  
Krishna Chaithanya Batchu ◽  
Valerie Laux ◽  
Michael Haertlein ◽  
...  
Keyword(s):  
Neutron Diffraction ◽  
Acyl Chain ◽  
Model Systems ◽  
Head Group ◽  
Single Class ◽  
Lipid Mixtures ◽  
Chain Composition ◽  
Acyl Chain Composition ◽  
The Impact

Eukaryotic and prokaryotic cell membranes are difficult to characterize directly with biophysical methods. Membrane model systems, that include fewer molecular species, are therefore often used to reproduce their fundamental chemical and physical properties. In this context, natural lipid mixtures directly extracted from cells are a valuable resource to produce advanced models of biological membranes for biophysical investigations and for the development of drug testing platforms. In this study we focused on single phospholipid classes, i.e. Pichia pastoris phosphatidylcholine (PC) and Escherichia coli phosphatidylglycerol (PG) lipids. These lipids were characterized by a different distribution of their respective acyl chain lengths and number of unsaturations. We produced both hydrogenous and deuterated lipid mixtures. Neutron diffraction experiments at different relative humidities were performed to characterize multilayers from these lipids and investigate the impact of the acyl chain composition on the structural organization. The novelty of this work resides in the use of natural extracts with a single class head-group and a mixture of chain compositions coming from yeast or bacterial cells. The characterization of the PC and PG multilayers showed that, as a consequence of the heterogeneity of their acyl chain composition, different lamellar phases are formed.

scholarly journals Visualization of domain formation in the inner and outer leaflets of a phospholipid bilayer.

1988 ◽  
Vol 106 (6) ◽  
pp. 1885-1892 ◽  
Author(s):  
D M Haverstick ◽  
M Glaser
Keyword(s):  
Phosphatidic Acid ◽  
Digital Image ◽  
Acyl Chain ◽  
Fluorescence Microscope ◽  
Phospholipid Bilayer ◽  
Domain Formation ◽  
Charge Coupled Device ◽  
Image Processor ◽  
Outer Leaflet ◽  
Naturally Occurring

Large vesicles (5-10-micron in diameter) were formed in the presence of phospholipids fluorescently labeled on the acyl chain and visualized using a fluorescence microscope, charge-coupled-device camera and digital image processor. When such vesicles contained a fluorescent phosphatidic acid (PA) and were exposed to 2 mM CaCl2 or 0.5 mM PrCl3, it was possible to visualize PA-enriched domains within the vesicles. Calcium-induced domain formation was reversible in the presence of 4 mM EGTA. Vesicles were formed containing fluorescent PA on either the inner or outer leaflet of the bilayer and the patching and dissolution of patching were studied under conditions where calcium was present on the outside of the vesicle and where calcium was distributed across the bilayer. In addition, vesicles were formed with two different fluorescent PA's, one on the inner leaflet and a different one on the outer leaflet of the bilayer. The results of the experiments show that in vesicles formed primarily with naturally occurring phospholipids such as egg phosphatidylcholine or brain phosphatidylethanolamine, there was no coordinate action of the two leaflets of the bilayer. An exception to this was found, however, if the vesicles were formed in the presence of primarily dioleoyl phospholipids (greater than 95 mol %). In these vesicles there was a coordinate or coupled response to calcium by the two leaflets of the bilayer. In most cases, however, the two leaflets of the bilayer showed independent or uncoupled domain formation.

scholarly journals Novel Insights and Mechanisms of Lipotoxicity-Driven Insulin Resistance

2020 ◽  
Vol 21 (17) ◽  
pp. 6358 ◽  
Author(s):  
Benjamin Lair ◽  
Claire Laurens ◽  
Bram Van Den Bosch ◽  
Cedric Moro
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Acyl Chain ◽  
The Body ◽  
Glucose Disposal ◽  
Tissue Lipid ◽  
Lipid Species ◽  
Chain Composition

A large number of studies reported an association between elevated circulating and tissue lipid content and metabolic disorders in obesity, type 2 diabetes (T2D) and aging. This state of uncontrolled tissue lipid accumulation has been called lipotoxicity. It was later shown that excess lipid flux is mainly neutralized within lipid droplets as triglycerides, while several bioactive lipid species such as diacylglycerols (DAGs), ceramides and their derivatives have been mechanistically linked to the pathogenesis of insulin resistance (IR) by antagonizing insulin signaling and action in metabolic organs such as the liver and skeletal muscle. Skeletal muscle and the liver are the main sites of glucose disposal in the body and IR in these tissues plays a pivotal role in the development of T2D. In this review, we critically examine recent literature supporting a causal role of DAGs and ceramides in the development of IR. A particular emphasis is placed on transgenic mouse models with modulation of total DAG and ceramide pools, as well as on modulation of specific subspecies, in relation to insulin sensitivity. Collectively, although a wide number of studies converge towards the conclusion that both DAGs and ceramides cause IR in metabolic organs, there are still some uncertainties on their mechanisms of action. Recent studies reveal that subcellular localization and acyl chain composition are determinants in the biological activity of these lipotoxic lipids and should be further examined.

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