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Conformational analysis of lipid membrane mimetics modified with Aβ42 peptide by Raman spectroscopy and computer simulations.

Peptide-lipid interactions play an important role in maintaining the integrity and function of the cell membrane. Even slight changes in these interactions can induce the development of various diseases. Specifically, peptide misfolding and aggregation in the membrane is considered to be one of the triggers of Alzheimer's disease (AD), however its exact mechanism is still unclear. To this end, an increase of amyloid-beta (Aβ) peptide concentration in the human brain is widely accepted to gradually produce cytotoxic Aβ aggregates (plaques). These plaques initiate a sequence of pathogenic events

Beyond electrostatics: Antimicrobial peptide selectivity and the influence of cholesterol-mediated fluidity and lipid chain length on protegrin-1 activity.

Antimicrobial peptides (AMPs) are a promising class of innate host defense molecules for next-generation antibiotics, as they uniquely target and permeabilize membranes of pathogens. This selectivity has been explained by the electrostatic attraction between these predominantly cationic peptides and the bacterial membrane, which is heavily populated with anionic lipids. However, AMP-resistant bacteria have non-electrostatic countermeasures that modulate membrane rigidity and thickness. We explore how variations in physical properties affect the membrane affinity and disruption process of prote

Membrane remodeling by α-synuclein and effects on amyloid formation.

α-Synuclein (α-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ∼20 nm). No discernible secondary structural changes were detected by circular dichroism

Allostery in a disordered protein: oxidative modifications to α-synuclein act distally to regulate membrane binding.

Both oxidative stress and aggregation of the protein α-synuclein (aS) have been implicated as key factors in the etiology of Parkinson's disease. Specifically, oxidative modifications to aS disrupt its binding to lipid membranes, an interaction considered critical to its native function. Here we seek to provide a mechanistic explanation for this phenomenon by investigating the effects of oxidative nitration of tyrosine residues on the structure of aS and its interaction with lipid membranes. Membrane binding is mediated by the first ∼95 residues of aS. We find that nitration of the single tyro

Effect of repetitive lysine-tryptophan motifs on the bactericidal activity of antimicrobial peptides.

Previous studies identified lysine- and tryptophan-rich sequences within various cationic antimicrobial peptides. In the present study, we s … ptides [(KW)(2) and (KW)(3)] strongly bound and partially inserted into negatively charged, anionic lipid bilayers. These longer peptides also induced membrane permeabilization and aggregation of lipid vesicles. The peptides had a disordered structure in aqueous solution, and only (KW)(4) and (KW)(5) displayed a folded conformation on lipid membranes. Moreover, …

Decyl-riboflavin: membrane-targeted lipophilic photosensitizer for lipid peroxidation and phototoxicity in HeLa cells under blue light irradiation.

Photodynamic therapy (PDT) exploits the controlled generation of reactive species to selectively destroy target cells, offering a minimally invasive alternative to conventional cancer and antimicrobial treatments. A key determinant of PDT efficacy is the ability of the photosensitizer (PS) to localize within lipid membranes, where proximity to polyunsaturated lipids maximizes oxidative damage. Riboflavin (Rf, Vitamin B2) is a biocompatible, naturally occurring PS with absorption in the blue light range; however, its inherent hydrophilicity limits membrane interaction. Here, we report the photo

How Influenza Virus Uses Host Cell Pathways during Uncoating.

Influenza is a zoonotic respiratory disease of major public health interest due to its pandemic potential, and a threat to animals and the human population. The influenza A virus genome consists of eight single-stranded RNA segments sequestered within a protein capsid and a lipid bilayer envelope. During host cell entry, cellular cues contribute to viral conformational changes that promote critical events such as fusion with late endosomes, capsid uncoating and viral genome release into the cytosol. In this focused review, we concisely describe the virus infection cycle and highlight the recen

Exploiting the message from cancer: the diagnostic value of extracellular vesicles for clinical applications.

Liquid biopsy is indispensable for the resolution of current medical issues, such as the cost of developing new drugs and predicting responses of patients to drugs. In this sense, not only the technology for liquid biopsy but also the target biomolecules for biomarkers need to be identified. Extracellular vesicles (EVs), which contain various proteins, including membrane-bound proteins, and RNAs, including mRNA and long/short noncoding RNAs, have emerged as ideal targets for liquid biopsy. These complex biomolecules are covered by a lipid bilayer, which can protect them from degradation. In th

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… Additionally, as we introduce later, EVs are a complex of RNA, proteins and other biomolecules that are covered by a lipid bilayer with transmembrane proteins. … Proteins are also contained in EVs and on EV lipid bilayers Fig. 2 Components of EVs. In EVs, various types of RNAs, such as small noncoding RNA, long noncoding RNA, and coding RNA and DNA are included. …

Small structural alterations greatly influence the membrane affinity of lipophilic ligands: Membrane interactions of bafilomycin A1 and its desmethyl derivative bearing 19F-labeling.

Molecular behavior under bilayer membrane environments is one of the important research topics concerning how organic molecules exert their biological activities when interacting with cellular membranes. However, chemistry-based approaches to this property have not been successful when compared with the structural biological strategy on ligand-receptor interactions. Here, we investigated the molecular behavior of the lipophilic ATPase inhibitor bafilomycin A1 and its derivatives under a lipid environment from a chemical point of view. Our results revealed significant differences in membrane af

Type 2 ryanodine receptors are highly sensitive to alcohol.

Exposure to ethanol levels reached in circulation during alcohol intoxication (>10mM) constricts cerebral arteries in rats and humans. Remarkably, targets and mechanisms underlying this action remain largely unidentified. Artery diameter is regulated by myocyte Ca(2+) sparks, a vasodilatory signal contributed to by type 2 ryanodine receptors (RyR2). Using laser confocal microscopy in rat cerebral arteries and bilayer electrophysiology we unveil that ethanol inhibits both Ca(2+) spark and RyR2 activity with IC50<20 mM, placing RyR2 among the ion channels that are most sensitive to ethanol. Alco

Peek-a-boo: membrane hijacking and the pathogenesis of viral hepatitis.

Historically, animal viruses have been classified on the basis of the presence or absence of an envelope - an external lipid bilayer membrane typically carrying one or more viral glycoproteins. However, growing evidence indicates that some 'non-enveloped' viruses circulate in the blood of infected individuals enveloped in host-derived membranes that provide protection from neutralizing antibodies. In this opinion article, we discuss this novel strategy for virus survival and consider how it contributes to the pathogenesis of acute viral hepatitis. The acquisition of an envelope by non-envelope

Lipid Loss Increases Stratum Corneum Stress and Drying Rates.

BACKGROUND: The lipid components and natural moisturizing factors (NMFs) of the stratum corneum (SC) are integral pieces of the self-regulating barrier strategy which comprises one of the most important functions of human skin and seems to be related to biomechanical responses of the SC. OBJECTIVES: This work presents the contributions of the lipid bilayers and NMFs to the barrier properties and mechanical responses of human SC. METHODS: We performed 2 biomechanical experiments, substrate curvature testing and double cantilever beam cohesion measurements, on isolated human SC exposed to eith…

In Silico Study of Ionizable Lipid Nanoparticles Using the SPICA Force Field.

Lipid nanoparticles (LNPs), composed of ionizable amino lipids, phosphatidylcholines (PC) lipids, and cholesterol, have shown promise as delivery vehicles for therapeutic oligonucleotides in various applications, including cancer immunotherapies, cellular reprogramming, genome editing, and viral vaccines (e.g., COVID-19 vaccines). However, the molecular characterization of ionizable amino lipids and their assemblies, such as LNPs, both in silico and in vitro, remains in its early stages. In particular, in silico studies on LNPs to understand their nanostructure have been limited due to the nee

The Lipid Flippases ALA4 and ALA5 Play Critical Roles in Cell Expansion and Plant Growth.

Aminophospholipid ATPases (ALAs) are lipid flippases involved in transporting specific lipids across membrane bilayers. Arabidopsis (Arabidopsis thaliana) contains 12 ALAs in five phylogenetic clusters, including four in cluster 3 (ALA4-ALA7). ALA4/5 and ALA6/7, are expressed primarily in vegetative tissues and pollen, respectively. Previously, a double knockout of ALA6/7 was shown to result in pollen fertility defects. Here we show that a double knockout of ALA4/5 results in dwarfism, characterized by reduced growth in rosettes (6.5-fold), roots (4.3-fold), bolts (4.5-fold), and hypocotyls (2

Latarcins: versatile spider venom peptides.

Arthropod venoms feature the presence of cytolytic peptides believed to act synergetically with neurotoxins to paralyze prey or deter aggres … estigate the spatial structure of Ltc in membrane-mimicking environments and their effects on model lipid bilayers. The antibacterial activity of Ltc was studied against a panel of Gram-negative and Gram-positive bacteria. In addition, the action of Ltc on erythrocytes and cancer cells was investigated in detail with confocal laser scanning microscopy. In the pr …

Effects of verbascoside, a phenylpropanoid glycoside from lemon verbena, on phospholipid model membranes.

Phenylpropanoid glycosides are water-soluble compounds widely distributed, most of them deriving from medicinal herbs. Among them, verbascoside or acteoside has exhibited a wide biological activity, being free radical scavenging the most representative one. Moreover, antitumor, antimicrobial, anti-inflammatory, anti-thrombotic and wound healing properties have been previously described. Herein, the interaction of verbascoside with phospholipid membranes has been studied by means of differential scanning calorimetry, fluorescence anisotropy and dynamic light scattering. Verbascoside showed stro

The comparative study of peroxidase activity and substrate binding properties of cytochrome P450 2B4 incorporated into phospholipid vesicles with the use of two different methods.

The comparative study of peroxidase activities and substrate binding properties of cytochrome p450 2B4 in reconstituted vesicles prepared with the use of two different techniques, and microsomal cytochrome P450 was carried out. The data obtained show that the two types of cytochrome P450 2B4-containing proteoliposomes do not differ substantially from each other with respect to H2O2- or cumene hydroperoxide-dependent substrate hydroxylation activities as well as substrate binding properties of hemoprotein reconstituted. However, some parameters measured with proteoliposomal cytochrome P450 are

The biochemical characteristics of stress-sensitive hypertensive rats.

The biological characteristics of a line of stress-sensitive hypertensive (SSH) rats genetically selected from Wistar rats are described, in particular the dynamics of arterial blood pressure and the biochemical properties of the Na(+)-K+ ATPase present in the outer renal medulla. Changes in the specific activity of this enzyme are discussed in terms of the lipid composition of the membrane bilayer and the amount of endogenous ouabain-like compounds present in the blood of the animals under study. Rats of both strains, Wistar and SSH, were studied under conditions of rest and stress (8 day reg

Facile and scalable fabrication of exosome-mimicking nanovesicles through PEGylated lipid detergent-aided cell extrusion.

We report a scalable fabrication method to generate exosome-mimicking nanovesicles (ENVs) by using a biocompatible, cell-binding lipid detergent during cell extrusion. A PEGylated mannosylerythritol lipid (MELPEG) detergent was rationally engineered to strongly associate with phospholipid membranes to increase cell membrane deformability and the corresponding friction force during extrusion and to enhance the dispersibility of ENVs. Compared to cell extrusion without detergent, cell extrusion in the presence of MELPEG increased the ENV production yield by approximately 20 times and cellular pr

Gold nanoparticles enable selective light-induced contents release from liposomes.

A novel proof of principle demonstration for contents release from liposomes that can be selectively activated by light irradiation is presented. The content release temperature was adjusted to slightly above body temperature, and hydrophobic or hydrophilic gold nanoparticles were incorporated into the lipid bilayer or the core of the liposomes, respectively. The release of a fluorescent marker was monitored upon exposure of the liposomes to UV light. Gold nanoparticle-containing liposomes remained intact at 37 degrees C but contents release was triggered by UV light-induced heating of the gol