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Anionic Phospholipid

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Frances Separovic – 1st expert on this subject based on the ideXlab platform

  • Anionic Phospholipid interactions of the prion protein n terminus are minimally perturbing and not driven solely by the octapeptide repeat domain
    Journal of Biological Chemistry, 2010
    Co-Authors: Martin Boland, Frances Separovic, Claire R Hatty, Andrew F Hill, Kevin J Barnham, Cathryn L Haigh, Michael N G James, Colin L Masters, Steven J Collins

    Abstract:

    Although the N terminus of the prion protein (PrPC) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23–110) and N2 (23–89) fragments derived from constitutive processing of PrPC and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the Anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for Anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.

  • effect of antimicrobial peptides from australian tree frogs on Anionic Phospholipid membranes
    Biophysical Journal, 2009
    Co-Authors: Frances Separovic, Johh D Gehman, John H Bowie, Marieisabel Aguilar

    Abstract:

    Skin secretions of numerous Australian tree frogs contain antimicrobial peptides that form part of the host defense mechanism against bacterial infection. The mode of action of these antibiotics is thought to be lysis of infectious organisms via cell membrane disruption, on the basis of vesicle-encapsulated dye leakage data [Ambroggio et al. (2005) Biophys. J. 89, 1874−1881]. A detailed understanding of the interaction of these peptides with bacterial membranes at a molecular level, however, is critical to their development as novel antibacterial therapeutics. We focus on four of these peptides, aurein 1.2, citropin 1.1, maculatin 1.1, and caerin 1.1, which exist as random coil in aqueous solution but have α-helical secondary structure in membrane mimetic environments. In our earlier solid-state NMR studies, only neutral bilayers of the zwitterionic Phospholipid dimyristoylphosphatidylcholine (DMPC) were used. Deuterated DMPC (d54-DMPC) was used to probe the effect of the peptides on the order of the lipi…

  • effect of antimicrobial peptides from australian tree frogs on Anionic Phospholipid membranes
    Biochemistry, 2008
    Co-Authors: Johh D Gehman, Kristopher Norman Hall, Martin Boland, Tara L Pukala, John H Bowie, Marieisabel Aguilar, Frances Separovic

    Abstract:

    Skin secretions of numerous Australian tree frogs contain antimicrobial peptides that form part of the host defense mechanism against bacterial infection. The mode of action of these antibiotics is thought to be lysis of infectious organisms via cell membrane disruption, on the basis of vesicle-encapsulated dye leakage data [Ambroggio et al. (2005) Biophys. J. 89, 1874-1881]. A detailed understanding of the interaction of these peptides with bacterial membranes at a molecular level, however, is critical to their development as novel antibacterial therapeutics. We focus on four of these peptides, aurein 1.2, citropin 1.1, maculatin 1.1, and caerin 1.1, which exist as random coil in aqueous solution but have α-helical secondary structure in membrane mimetic environments. In our earlier solid-state NMR studies, only neutral bilayers of the zwitterionic Phospholipid dimyristoylphosphatidylcholine (DMPC) were used. Deuterated DMPC (d 54 -DMPC) was used to probe the effect of the peptides on the order of the lipid acyl chains and dynamics of the Phospholipid headgroups by deuterium and 31 P NMR, respectively. In this report we demonstrate several important differences when Anionic Phospholipid is included in model membranes. Peptide-membrane interactions were characterized using surface plasmon resonance (SPR) spectroscopy and solid-state nuclear magnetic resonance (NMR) spectroscopy. Changes in Phospholipid motions and membrane binding information provided additional insight into the action of these antimicrobial peptides. While this set of peptides has significant C- and N-terminal sequence homology, they vary in their mode of membrane interaction. The longer peptides caerin and maculatin exhibited properties that were consistent with transmembrane insertion while citropin and aurein demonstrated membrane disruptive mechanisms. Moreover, aurein was unique with greater perturbation of neutral versus Anionic membranes. The results are consistent with a surface interaction for aurein 1.2 and pore formation rather than membrane lysis by the longer peptides.

Miriam L Greenberg – 2nd expert on this subject based on the ideXlab platform

  • Deficiency in mitochondrial Anionic Phospholipid synthesis impairs cell wall biogenesis.
    Biochemical Society transactions, 2020
    Co-Authors: Q Zhong, Miriam L Greenberg

    Abstract:

    Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1, which encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial Anionic Phospholipids phosphatidylglycerol and CL. The pgs1Delta mutant exhibits severe growth defects at 37 degrees C. To understand the essential functions of mitochondrial Anionic lipids at elevated temperatures, we isolated suppressors of pgs1Delta that grew at 37 degrees C. The present review summarizes our analysis of suppression of pgs1Delta growth defects by a mutant that has a loss-of-function mutation in KRE5, a gene involved in cell wall biogenesis.

  • deficiency in mitochondrial Anionic Phospholipid synthesis impairs cell wall biogenesis
    Biochemical Society Transactions, 2005
    Co-Authors: Q Zhong, Miriam L Greenberg

    Abstract:

    Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1 ,w hich encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial Anionic Phospholipids phosphatidylglycerol and CL. The pgs1∆ mutant exhibits severe growth defects at 37 ◦ C. To understand the essential functions of mitochondrial Anionic lipids at elevated temperatures, we isolated suppressors of pgs1∆ that grew at 37 ◦ C. The present review summarizes our analysis of suppression of pgs1∆ growth defects by a mutant that has a loss-of-function mutation in KRE5, a gene involved in cell

  • Deficiency in mitochondrial Anionic Phospholipid synthesis impairs cell wall biogenesis
    Biochemical Society Transactions, 2005
    Co-Authors: Q Zhong, Miriam L Greenberg

    Abstract:

    Cardiolipin (CL) is the signature lipid of the mitochondrial membrane and plays a key role in mitochondrial physiology and cell viability. The importance of CL is underscored by the finding that the severe genetic disorder Barth syndrome results from defective CL composition and acylation. Disruption of PGS1, which encodes the enzyme that catalyses the committed step of CL synthesis, results in loss of the mitochondrial Anionic Phospholipids phosphatidylglycerol and CL. The pgs1Δ mutant exhibits severe growth defects at 37°C. To understand the essential functions of mitochondrial Anionic lipids at elevated temperatures, we isolated suppressors of pgs1Δ that grew at 37°C. The present review summarizes our analysis of suppression of pgs1Δ growth defects by a mutant that has a loss-of-function mutation in KRE5, a gene involved in cell wall biogenesis.

Jose Requejoisidro – 3rd expert on this subject based on the ideXlab platform

  • a complex interplay of Anionic Phospholipid binding regulates 3 phosphoinositide dependent kinase 1 homodimer activation
    Scientific Reports, 2019
    Co-Authors: Gloria De Las Herasmartinez, Banafshe Larijani, Veronique Calleja, Remy Bailly, Jean Dessolin, Jose Requejoisidro

    Abstract:

    3′-Phosphoinositide-dependent-Kinase-1 (PDK1) is a master regulator whereby its PI3-kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for PtdIns(3,4,5)P3 and other Anionic Phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete. Using advanced quantitative-time-resolved imaging (Fluorescence Lifetime Imaging and Fluorescence Correlation Spectroscopy) and molecular modelling, we show an interplay of antagonistic binding effects of PtdIns(3,4,5)P3 and other Anionic Phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal and conformational dynamics of PDK1 and the activation of its downstream substrates. We have established a new AnionicPhospholipid-dependent model for PDK1 regulation, depicting the conformational dynamics of multiple homodimer states. We show that the dysregulation of the PI3K pathway perturbs equilibrium between the PDK1 homodimer conformations. Our findings provide a role for the PtdSer binding site and its previously unrewarding role in PDK1 downregulation, suggesting a possible therapeutic strategy where the constitutively active dimer conformer of PDK1 may be rendered inactive by small molecules that drive it to its PtdSer-bound conformer.

  • a complex interplay of Anionic Phospholipid binding regulates 3 phosphoinositide dependent kinase 1 homodimer activation
    bioRxiv, 2019
    Co-Authors: G De Las Heras, Veronique Calleja, Remy Bailly, Jean Dessolin, Jose Requejoisidro, Banafshe Larijani

    Abstract:

    3-Phosphoinositide-dependent-Kinase-1 is a master regulator whereby its PI3- kinase-dependent dysregulation in human pathologies is well documented. Understanding the direct role for PtdIns(3,4,5)P3 and other Anionic Phospholipids in the regulation of PDK1 conformational dynamics and its downstream activation remains incomplete. Using advanced quantitative-time-resolved imaging, FCS and molecular modelling, we show an interplay of antagonistic binding effects of PtdIns(3,4,5)P3 and other Anionic Phospholipids, regulating activated PDK1 homodimers. We demonstrate that phosphatidylserine maintains PDK1 in an inactive conformation. The dysregulation of the PI3K pathway affects the spatio-temporal and conformational dynamics of PDK1 and the activation of its downstream substrates. We establish an AnionicPhospholipid-dependent model for PDK1 regulation, depicting the conformational dynamics of multiple homodimer states. The dysregulation of the PI3K pathway perturbs equilibrium between the PDK1 homodimer conformations. Our findings indicate that the alteration of specific basic residues of PDK1-PH domain leads to its constitutive activation, potential significance in different types of carcinomas.