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Ananicoleta Bondar - One of the best experts on this subject based on the ideXlab platform.
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potential energy function for a photo switchable Lipid Molecule
Journal of Computational Chemistry, 2020Co-Authors: Oskar Klaja, James A Frank, Dirk Trauner, Ananicoleta BondarAbstract:Photo-switchable Lipids are synthetic Lipid Molecules used in photo-pharmacology to alter membrane lateral pressure and thus control opening and closing of mechanosensitive ion channels. The molecular picture of how photo-switchable Lipids interact with membranes or ion channels is poorly understood. To facilitate all-atom simulations that could provide a molecular picture of membranes with photo-switchable Lipids, we derived force field parameters for atomistic computations of the azobenzene-based fatty acid FAAzo-4. We implemented a Phyton-based algorithm to make the optimization of atomic partial charges more efficient. Overall, the parameters we derived give good description of the equilibrium structure, torsional properties, and non-bonded interactions for the photo-switchable Lipid in its trans and cis intermediate states, and crystal lattice parameters for trans-FAAzo-4. These parameters can be extended to all-atom descriptions of various photo-switchable Lipids that have an azobenzene moiety.
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Lipid coupled docking of transmembrane substrate by the glpg rhomboid protease from escherichia coli
Biophysical Journal, 2012Co-Authors: Ananicoleta Bondar, Stephen H. WhiteAbstract:Intramembrane proteases cleave transmembrane (TM) substrates within the plane of the Lipid membrane. The GlpG rhomboid protease appears to dock its TM substrates by opening laterally towards the membrane a gate formed by helix 5. A crystal structure thought to represent GlpG in a closed state indicates a Lipid headgroup bound to the catalytic site. Since the Lipid must unbind for the substrate to dock, the questions arise as to how fast does Lipid unbinding occur, and whether there is coupling between the incoming TM substrate and the Lipid bound to the active site. To address these questions we performed systematic molecular dynamics (MD) simulations of GlpG in the absence of a TM substrate, and with TM substrate at various locations relative to GlpG. We find that, indeed, the presence of the substrate causes the Lipid:active site interactions to weaken rapidly, in several tens of nanoseconds. That is, the incoming substrate prepares the enzyme for docking by inducing the displacement of the active-site Lipid. The structure and dynamics of the substrate docking region of GlpG depend not only on whether or not a Lipid Molecule is bound to the active site, but also on the presence of the TM substrate. Our results on the Lipid-coupled docking of the substrate to GlpG reveal an unsuspected complexity of the Lipid interactions of intramembrane proteases.This research was supported in part by the National Institute of General Medical Sciences (GM-74637 and GM-86685 to S.H.W) and an allocation of computer time from the National Science Foundation through the TeraGrid resources at TACC (Ranger).
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Lipid mediated helix gating in the glpg rhomboid protease from escherichia coli
Biophysical Journal, 2011Co-Authors: Stephen H. White, Ananicoleta BondarAbstract:Intramembrane proteases cleave transmembrane substrates to liberate Molecules that participate in essential cellular processes, such as cell signaling and gene regulation. Understanding how intramembrane proteases work requires knowledge of how substrates are docked and cleaved within the membrane plane. We find that Lipid interactions and the presence of the substrate affect significantly the structure and dynamics of the helical gate and of the cap loop that control access to the active site of the GlpG rhomboid protease from E. coli.In the absence of the substrate, the 1-palmytoyl-2-oleoyl-sn-glycero-3-phosphatidyethanolamine (POPE) Lipid Molecule bound to the protease active site remains closely associated with the protease on the ∼90ns timescale of the molecular dynamics (MD) simulation. Presence of the Spitz transmembrane substrate perturbs the interactions between the protease and the active-site Lipid Molecule. The substrate and whether or not a Lipid headgroup is bound to the active site affect the orientation of the lateral gate helix 5 relative to the rest of the protein, the structure and dynamics of the cap loop, and the interaction between the catalytic serine and water. This suggests that Lipid Molecules may be involved in controlling the access to the active site of intramembrane proteases.This research was supported in part by the National Institute of General Medical Sciences (GM-74637 and GM-86685 to S.H.W) and an allocation of computer time from the National Science Foundation through the TeraGrid resources at TACC (Ranger).
S K Burley - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the mus musculus cholesterol regulated start protein 4 stard4 containing a star related Lipid transfer domain
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Michael J Romanowski, Raymond E Soccio, Jan L Breslow, S K BurleyAbstract:The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-A resolution, revealing a compact α/β structure related to the START domain present in the cytoplasmic C-terminal portion of human MLN64. The volume of the putative Lipid-binding tunnel was estimated at 847 A 3 , which is consistent with the binding of one cholesterol-size Lipid Molecule. Comparison of the tunnel-lining residues in StarD4 and MLN64-START permitted identification of possible Lipid specificity determinants in both molecular tunnels. Homology modeling of related proteins, and comparison of the StarD4 and MLN64-START structures, showed that StarD4 is a member of a large START domain superfamily characterized by the helix-grip fold. Additional mechanistic and evolutionary studies should be facilitated by the availability of a second START domain structure from a distant relative of MLN64.
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crystal structure of the mus musculus cholesterol regulated start protein 4 stard4 containing a star related Lipid transfer domain
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Michael J Romanowski, Raymond E Soccio, Jan L Breslow, S K BurleyAbstract:The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-A resolution, revealing a compact alpha/beta structure related to the START domain present in the cytoplasmic C-terminal portion of human MLN64. The volume of the putative Lipid-binding tunnel was estimated at 847 A(3), which is consistent with the binding of one cholesterol-size Lipid Molecule. Comparison of the tunnel-lining residues in StarD4 and MLN64-START permitted identification of possible Lipid specificity determinants in both molecular tunnels. Homology modeling of related proteins, and comparison of the StarD4 and MLN64-START structures, showed that StarD4 is a member of a large START domain superfamily characterized by the helix-grip fold. Additional mechanistic and evolutionary studies should be facilitated by the availability of a second START domain structure from a distant relative of MLN64.
Yasuyuki Igarashi - One of the best experts on this subject based on the ideXlab platform.
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mouse sphingosine kinase isoforms sphk1a and sphk1b differ in enzymatic traits including stability localization modification and oligomerization
Journal of Biological Chemistry, 2006Co-Authors: Akio Kihara, Yoshihiro Anada, Yasuyuki IgarashiAbstract:Sphingosine kinases catalyze the production of the bioactive Lipid Molecule sphingosine 1-phosphate. Mice have two isoforms of sphingosine kinase type 1, SPHK1a and SPHK1b. In addition to the previously reported difference in their enzyme activities, we have found that these isoforms differ in several enzymatic characteristics. First, SPHK1b is unstable, whereas SPHK1a is highly stable. Degradation of SPHK1b occurs at the membrane and is inhibited by a proteasome inhibitor. Second, only SPHK1b exhibits abnormal mobility on SDS-PAGE, probably due to its SDS-resistant structure. Third, SPHK1a and SPHK1b are predominantly detected in the soluble and membrane fractions, respectively, when their degradation is inhibited. Fourth, only SPHK1b is modified with Lipid, on its unique Cys residues (Cys-4 and Cys-5). Site-directed mutagenesis at these Cys residues resulted in increased sphingosine kinase activity, suggesting that the modification is inhibitory to the enzyme. Finally, SPHK1b tends to form homo-oligomers, whereas most SPHK1a is presented as monomers. We have also determined that the Lipid modification of SPHK1b is involved in its homo-oligomerization. Thus, although these two proteins differ only in a few N-terminal amino acid residues, their enzymatic traits are extremely different.
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sphingosine 1 phosphate lyase spl is an endoplasmic reticulum resident integral membrane protein with the pyridoxal 5 phosphate binding domain exposed to the cytosol
Biochemical and Biophysical Research Communications, 2004Co-Authors: Mika Ikeda, Akio Kihara, Yasuyuki IgarashiAbstract:Sphingosine-1-phosphate (S1P) is a sphingoLipid metabolite that functions as a bioactive Lipid Molecule. S1P is degraded either by S1P lyase or by S1P phosphohydrolase. The gene encoding mammalian S1P lyase, SPL, has been identified. Here, we characterize the SPL protein in its expression, localization, and topology. The expression levels of the SPL protein correlated well with the dihydrosphingosine-1-phosphate (DHS1P) lyase activity in most tissues. However, liver and heart exhibited high DHS1P lyase activities compared to their SPL protein levels. The SPL mRNA expression was temporally regulated during mouse embryonal development. Immunofluorescence microscopy demonstrated that SPL is localized at the endoplasmic reticulum. Proteinase K digestion studies revealed that the large hydrophilic domain, containing the active site, faces the cytosol. This active site orientation is opposite to that of S1P phosphohydrolase, indicating that the degradation of S1P by two S1P-degrading enzymes occurs in spatially separated sides of the endoplasmic reticulum.
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Sphingosine-1-phosphate lyase is involved in the differentiation of F9 embryonal carcinoma cells to primitive endoderm.
The Journal of biological chemistry, 2003Co-Authors: Akio Kihara, Mika Ikeda, Yuki Kariya, Eun-young Lee, Yong-moon Lee, Yasuyuki IgarashiAbstract:Abstract Sphingosine 1-phosphate (S1P) is a bioactive Lipid Molecule that acts both extracellularly and intracellularly. TheSPL gene encodes a mammalian S1P lyase that degrades S1P. Here, we have disrupted the SPL gene in mouse F9 embryonal carcinoma cells by gene targeting. This is the first report of gene disruption of mammalian S1P lyase. The SPL-null cells exhibited no S1P lyase activity, and intracellular S1P was increased ∼2-fold, compared with wild-type cells. Treatment of F9 embryonal carcinoma cells with retinoic acid induces differentiation to primitive endoderm (PrE). An acceleration in this PrE differentiation was observed in the SPL-null cells. This effect was apparently caused by the accumulated S1P, sinceN,N-dimethylsphingosine, a S1P synthesis inhibitor, had an inhibitory effect on the PrE differentiation. Moreover, F9 cells stably expressing sphingosine kinase also exhibited an acceleration in the differentiation. Exogenous S1P had no effect on differentiation, indicating that intracellular but not extracellular S1P is involved. Moreover, we determined that expression of the SPL protein is up-regulated during the progression to PrE. We also showed that sphingosine kinase activity is increased in PrE-differentiated cells. These results suggest that intracellular S1P has a role in the PrE differentiation and that SPL may be involved in the regulation of intracellular S1P levels during this differentiation.
Michael J Romanowski - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the mus musculus cholesterol regulated start protein 4 stard4 containing a star related Lipid transfer domain
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Michael J Romanowski, Raymond E Soccio, Jan L Breslow, S K BurleyAbstract:The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-A resolution, revealing a compact α/β structure related to the START domain present in the cytoplasmic C-terminal portion of human MLN64. The volume of the putative Lipid-binding tunnel was estimated at 847 A 3 , which is consistent with the binding of one cholesterol-size Lipid Molecule. Comparison of the tunnel-lining residues in StarD4 and MLN64-START permitted identification of possible Lipid specificity determinants in both molecular tunnels. Homology modeling of related proteins, and comparison of the StarD4 and MLN64-START structures, showed that StarD4 is a member of a large START domain superfamily characterized by the helix-grip fold. Additional mechanistic and evolutionary studies should be facilitated by the availability of a second START domain structure from a distant relative of MLN64.
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crystal structure of the mus musculus cholesterol regulated start protein 4 stard4 containing a star related Lipid transfer domain
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Michael J Romanowski, Raymond E Soccio, Jan L Breslow, S K BurleyAbstract:The x-ray structure of the mouse cholesterol-regulated START protein 4 (StarD4) has been determined at 2.2-A resolution, revealing a compact alpha/beta structure related to the START domain present in the cytoplasmic C-terminal portion of human MLN64. The volume of the putative Lipid-binding tunnel was estimated at 847 A(3), which is consistent with the binding of one cholesterol-size Lipid Molecule. Comparison of the tunnel-lining residues in StarD4 and MLN64-START permitted identification of possible Lipid specificity determinants in both molecular tunnels. Homology modeling of related proteins, and comparison of the StarD4 and MLN64-START structures, showed that StarD4 is a member of a large START domain superfamily characterized by the helix-grip fold. Additional mechanistic and evolutionary studies should be facilitated by the availability of a second START domain structure from a distant relative of MLN64.
Ronald N Mcelhaney - One of the best experts on this subject based on the ideXlab platform.
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membrane Lipid phase transitions and phase organization studied by fourier transform infrared spectroscopy
Biochimica et Biophysica Acta, 2013Co-Authors: Ruthven N A H Lewis, Ronald N McelhaneyAbstract:Abstract Fourier transform infrared (FTIR) spectroscopy is a powerful yet relatively inexpensive and convenient technique for studying the structure and organization of membrane Lipids in their various polymorphic phases. This spectroscopic technique yields information about the conformation and dynamics of all regions of the Lipid Molecule simultaneously without the necessity of introducing extrinsic probes. In this review, we summarize some relatively recent FTIR spectroscopic studies of the structure and organization primarily of fully hydrated phosphoLipids in their biologically relevant lamellar crystalline, gel and liquid–crystalline phases, and show that interconversions between these bilayer phases can be accurately monitored by this technique. We also briefly discuss how the structure and organization of potentially biologically relevant nonlamellar micellar or reversed hexagonal Lipid phases can be studied and how phase transitions between lamellar and nonlamellar phases, or between various nonlamellar phases, can be followed as well. In addition, we discuss the potential for FTIR spectroscopy to yield fairly high resolution structural information about phosphoLipid packing in lamellar crystalline or gel phases. Finally, we show that many, but not all of these FTIR approaches can also yield valuable information about Lipid–protein interactions in membrane protein- or peptide-containing Lipid membrane bilayer model or even in biological membranes. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies.
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fourier transform infrared spectroscopic studies of the interaction of the antimicrobial peptide gramicidin s with Lipid micelles and with Lipid monolayer and bilayer membranes
Biochemistry, 1999Co-Authors: Ruthven N A H Lewis, Elmar J Prenner, Leslie H Kondejewski, Carol R Flach, Richard Mendelsohn, Robert S Hodges, Ronald N McelhaneyAbstract:We have utilized Fourier transform infrared spectroscopy to study the interaction of the antimicrobial peptide gramicidin S (GS) with Lipid micelles and with Lipid monolayer and bilayer membranes as a function of temperature and of the phase state of the Lipid. Since the conformation of GS does not change under the experimental conditions employed in this study, we could utilize the dependence of the frequency of the amide I band of the central beta-sheet region of this peptide on the polarity and hydrogen-bonding potential of its environment to probe GS interaction with and location in these Lipid model membrane systems. We find that the GS is completely or partially excluded from the gel states of all of the Lipid bilayers examined in this study but strongly partitions into Lipid micelles, monolayers, or bilayers in the liquid-crystalline state. Moreover, in general, the penetration of GS into zwitterionic and uncharged Lipid bilayer coincides closely with the gel to liquid-crystalline phase transition of the Lipid. However, GS begins to penetrate into the gel-state bilayers of anionic phosphoLipids prior to the actual chain-melting phase transition, while in cationic Lipid bilayers, GS does not partition strongly into the liquid-crystalline bilayer until temperatures well above the chain-melting phase transition are reached. In the liquid-crystalline state, the polarity of the environment of GS indicates that this peptide is located primarily at the polar/apolar interfacial region of the bilayer near the glycerol backbone region of the Lipid Molecule. However, the depth of GS penetration into this interfacial region can vary somewhat depending on the structure and charge of the Lipid Molecule. In general, GS associates most strongly with and penetrates most deeply into more disordered bilayers with a negative surface charge, although the detailed chemical structure of the Lipid Molecule and physical organization of the Lipid aggregate (micelle versus monolayer versus bilayer) also have minor effects on these processes.