Pardaxin induces aggregation but not fusion of phosphatidylserine vesicles

Lelkes, Peter I.; Lazarovici, Philip

doi:10.1016/0014-5793(88)80656-2

Cited by 15 publications

(5 citation statements)

References 31 publications

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“…Numerous studies have addressed the interaction of pardaxin with lipid membranes (7-14,30-36), but have not been based on detailed kinetic studies-focusing instead on endpoint permeation (8)(9)(10)31,33). We extend these studies by a methodical investigation of how the rate of vesicle permeabilization (calcein release) is affected by solution pH and lipid headgroup charge.…”

Section: Calcein Release Patterns Are Dependent On Lipid Headgroup Chmentioning

confidence: 99%

Pardaxin Permeabilizes Vesicles More Efficiently by Pore Formation than by Disruption

Vad

Bertelsen

Johansen

et al. 2010

Biophysical Journal

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Pardaxin is a 33-amino-acid neurotoxin from the Red Sea Moses sole Pardachirus marmoratus, whose mode of action shows remarkable sensitivity to lipid chain length and charge, although the effect of pH is unclear. Here we combine optical spectroscopy and dye release experiments with laser scanning confocal microscopy and natural abundance (13)C solid-state nuclear magnetic resonance to provide a more complete picture of how pardaxin interacts with lipids. The kinetics and efficiency of release of entrapped calcein is highly sensitive to pH. In vesicles containing zwitterionic lipids (PC), release occurs most rapidly at low pH, whereas in vesicles containing 20% anionic lipid (PG), release occurs most rapidly at high pH. Pardaxin forms stable or transient pores in PC vesicles that allow release of contents without loss of vesicle integrity, whereas the inclusion of PG promotes total vesicle collapse. In agreement with this, solid-state nuclear magnetic resonance reveals that pardaxin takes up a trans-membrane orientation in 14-O-PC/6-O-PC bicelles, whereas the inclusion of 14-0-PG restricts it to contacts with lipid headgroups, promoting membrane lysis. Pore formation in zwitterionic vesicles is more efficient than lysis of anionic vesicles, suggesting that electrostatic interactions may trap pardaxin in several suboptimal interconverting conformations on the membrane surface.

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Section: Calcein Release Patterns Are Dependent On Lipid Headgroup Chmentioning

confidence: 99%

Pardaxin Permeabilizes Vesicles More Efficiently by Pore Formation than by Disruption

Vad

Bertelsen

Johansen

et al. 2010

Biophysical Journal

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“…Pardaxin was synthesized and showed the same biological activity as the natural form [22]. With pore-forming ability on lipid membranes [23], pardaxin demonstrated various potential antibacterial, antiviral, and neurotoxic activities [22–25]. Our previous study revealed that pardaxin induced apoptosis in human cervical adenocarcinoma HeLa cells [26].…”

Section: Introductionmentioning

confidence: 99%

Pardaxin, an Antimicrobial Peptide, Triggers Caspase-Dependent and ROS-Mediated Apoptosis in HT-1080 Cells

2011

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Pardaxin is an antimicrobial peptide (AMP) that was first isolated from secretions of the Red Sea Moses sole. The role of pardaxin in inducing apoptosis for preventing cancer has not yet been investigated. In the present study, we examined the antitumor activity of pardaxin against human fibrosarcoma HT-1080 cells; pardaxin inhibited cell proliferation by inducing apoptosis, as demonstrated by an increase in the externalization of plasma membrane phosphatidylserine and the presence of chromatin condensation. Additionally, pardaxin-treated cells showed elevation of caspase-3/7 activities, disruption of the mitochondrial membrane potential, and accumulation of reactive oxygen species (ROS) production. Inhibition of ROS production and caspase-3/7 activities reduced pardaxin-induced effects. Taken together, these findings suggest that pardaxin may be a potential anticancer agent for selectively inducing apoptosis in cancer cells.

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“…These findings are in agreement with previous studies by CD spectroscopy, which reported that in H 2 O, pardaxin is mostly unstructured, although it adopts a helical conformation upon addition of increasing amounts of TFE (37,38,57,58). We chose DPC micelles for this work because of the affinity of pardaxins for membranes containing phosphatidylcholine (12,39). In DPC detergent micelles, Pa4 is soluble up ϳ1.0 mM.…”

Section: Structure Of Pardaxin In Micelles-pardaxinmentioning

confidence: 99%

Structure and Orientation of Pardaxin Determined by NMR Experiments in Model Membranes

Porcelli

Buck

Lee

et al. 2004

Journal of Biological Chemistry

164

149

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Pardaxins are a class of ichthyotoxic peptides isolated from fish mucous glands. Pardaxins physically interact with cell membranes by forming pores or voltage-gated ion channels that disrupt cellular functions. Here we report the high-resolution structure of synthetic pardaxin Pa4 in sodium dodecylphosphocholine micelles, as determined by 1 H solution NMR spectroscopy. The peptide adopts a bend-helix-bend-helix motif with an angle between the two structure helices of 122 ؎ 9°, making this structure substantially different from the one previously determined in organic solvents. In addition, paramagnetic solution NMR experiments on Pa4 in micelles reveal that except for the C terminus, the peptide is not solventexposed. These results are complemented by solid-state NMR experiments on Pa4 in lipid bilayers. In particular, Pardaxins belong to a class of small amphipathic peptides that form part of the defense mechanism secreted by sole fish of the genus Pardachirus (1). These polypeptides are postulated to be shark-repelling and toxic to several different organisms (2, 3). The physiology and pharmacology of pardaxins is rather complex; their effects range from interference with ionic transport in both the epithelium and nerve cells to morphological changes in the synaptic vesicles of lipid membranes (4 -6). At minimum inhibitory concentrations (3 to 40 M), pardaxins are able to kill bacteria, whereas at higher concentrations (Ͼ50 M), they lyse red blood cell membranes. In addition, pardaxins can disrupt the ionic transport of the osmoregulatory epithelium and presynaptic activity in mammals by forming voltage-dependent and ion-selective channels (1,7,8).An important characteristic of these membrane active peptides is their selective interaction with specific lipid membranes. Several mechanistic studies carried out with synthetic lipids suggest that pardaxins interact with the lipid surface by aggregating and forming pores, and eventually causing leakage of the cellular content (4). The widely accepted mechanism for pardaxin interactions with these membranes is the so-called "barrel-stave" model. This is a multistep mechanism in which the peptides are thought to a) bind the membrane in an ␣-helical structure, b) self-aggregate on the membrane surface, c) insert themselves into the hydrocarbon core of the membrane, and d) recruit more monomers, progressively increasing the size of the pore. Helicity, hydrophobic moment, hydrophobicity, charges, and the angle subtended by the hydrophilic/hydrophobic helix surfaces are all crucial structural parameters that modulate both the activity and selectivity of these membrane active peptides (9, 10).Several biophysical studies show that the known sequences of pardaxins (Fig.

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Pardaxin induces aggregation but not fusion of phosphatidylserine vesicles

Cited by 15 publications

References 31 publications

Pardaxin Permeabilizes Vesicles More Efficiently by Pore Formation than by Disruption

Pardaxin Permeabilizes Vesicles More Efficiently by Pore Formation than by Disruption

Pardaxin, an Antimicrobial Peptide, Triggers Caspase-Dependent and ROS-Mediated Apoptosis in HT-1080 Cells

Structure and Orientation of Pardaxin Determined by NMR Experiments in Model Membranes

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