β2-Microglobulin amyloid fibril-induced membrane disruption is enhanced by endosomal lipids and acidic pH.

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of β2-microglobulin (β2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which β2m-lipid interactions occur have not been investigated previously.

Aggregation modulators interfere with membrane interactions of β2-microglobulin fibrils.

Amyloid fibril accumulation is a pathological hallmark of several devastating disorders, including Alzheimer's disease, prion diseases, type II diabetes, and others. Although the molecular factors responsible for amyloid pathologies have not been deciphered, interactions of misfolded proteins with cell membranes appear to play important roles in these disorders. Despite increasing evidence for the involvement of membranes in amyloid-mediated cytotoxicity, the pursuit for therapeutic strategies has focused on preventing self-assembly of the proteins comprising the amyloid plaques.

N-terminal aromatic residues closely impact the cytolytic activity of cupiennin 1a, a major spider venom peptide.

Cupiennins are small cationic α-helical peptides from the venom of the ctenid spider Cupiennius salei which are characterized by high bactericidal as well as hemolytic activities. To gain insight into the determinants responsible for the broad cytolytic activities, two analogues of cupiennin 1a with different N-terminal hydrophobicities were designed. The insecticidal, bactericidal and hemolytic activities of these analogues were assayed and compared to the native peptide.

Direct three-dimensional visualization of membrane disruption by amyloid fibrils.

Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer's, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils.

Heparin inhibits membrane interactions and lipid-induced fibrillation of a prion amyloidogenic determinant.

Glycosaminoglycans (GAGs), particularly heparin, are known to reduce the toxicities of various amyloidogenic proteins. The molecular factors underlying the antitoxic effects of GAGs, however, are still not fully understood. Because interactions of amyloidogenic proteins and their aggregates with membranes are believed to play major roles in affecting amyloid pathogenesis, our objective in this study was to elucidate the effect of heparin on membrane interactions of the 21-residue amyloidogenic determinant of the prion protein [PrP(106-126)].

Lipid-induced calcitonin fibrillation blocks membrane interactions of a peptide antibiotic.

Interactions between membranes and amyloid proteins are believed to be a major factor contributing to pathogenesis in amyloid diseases. Furthermore, membranes have been shown to closely affect fibrillation processes of varied amyloidogenic peptides. Here we describe an intriguing phenomenon in which bilayer-induced fibrillation of human calcitonin (hCT) gave rise to significant inhibition of membrane interactions of alamethicin, an antibiotic, membrane-permeating peptide.

Specific mutations alter fibrillation kinetics, fiber morphologies, and membrane interactions of pentapeptides derived from human calcitonin.

Protein misfolding and fibrillation are fundamental facets underlying a diverse group of amyloid disorders and diseases. The molecular factors responsible for amyloid protein toxicity and pathological consequences, however, are still not fully understood. The involvement of specific residues or sequence elements in fibril formation and the interactions of amyloid protein aggregates with membranes are believed to constitute two critical parameters contributing to amyloidogenesis and amyloid pathologies.

Amyloid - membrane interactions: experimental approaches and techniques.

The growing interest in membrane interactions of amyloidogenic peptides and proteins emanates from the realization that lipids and membranes play important, potentially central, roles in the toxicity and pathological pathways of amyloid diseases. Expanding body of evidence indicates that lipid binding of amyloidogenic peptides and amyloid peptide association with cellular membranes is critical in the onset and progression of amyloid diseases. Advancing the understanding in this field goes hand in hand with application of varied biophysical and biological techniques designed to probe the characteristics and underlying mechanisms of membrane-peptide interactions.

Mechanisms of alpha-defensin bactericidal action: comparative membrane disruption by Cryptdin-4 and its disulfide-null analogue.

Mammalian alpha-defensins all have a conserved triple-stranded beta-sheet structure that is constrained by an invariant tridisulfide array, and the peptides exert bactericidal effects by permeabilizing the target cell envelope. Curiously, the disordered, disulfide-null variant of mouse alpha-defensin cryptdin-4 (Crp4), termed (6C/A)-Crp4, has bactericidal activity equal to or greater than that of the native peptide, providing a rationale for comparing the mechanisms by which the peptides interact with and disrupt phospholipid vesicles of defined composition. For both live Escherichia coli ML35 cells and model membranes, disordered (6C/A)-Crp4 induced leakage in a manner similar to that of Crp4 but had less overall membrane permeabilizing activity.

Membrane interactions and lipid binding of casein oligomers and early aggregates.

Caseins constitute the main protein components in mammalian milk and have critical functions in calcium transport and prevention of protein aggregation. Fibrillation and aggregation of kappa-casein, a phenomenon which has only recently been detected, might be associated with malfunctions of milk secretion and amyloidosis phenomena in the mammary glands. This study employs a newly-designed chromatic biomimetic vesicle assay to investigate the occurrence and the parameters affecting membrane interactions of casein aggregates and the contribution of individual casein members to membrane binding.

Effect of structural and conformation modifications, including backbone cyclization, of hydrophilic hexapeptides on their intestinal permeability and enzymatic stability.

A library of 18 hexapeptide analogs was synthesized, including sub-libraries of N- or C-methylation of the parent hexapeptide Phe-Gly-Gly-Gly-Gly-Phe, as well as backbone cyclized analogs of each linear analog with various ring sizes. N- or C-methylation as well as cyclization (but not backbone cyclization) have been suggested to improve intestinal permeability and metabolic stability of peptides in general. Here we aimed to assess their applicability to hydrophilic peptides.

Glass-supported lipid/polydiacetylene films for colour sensing of membrane-active compounds.

Glass-supported biomimetic lipid/polydiacetylene films were employed for colourimetric detection and analysis of amphiphilic and membrane-active molecules. The sensor films comprise lipid monolayers that constitute a biomimetic membrane platform, interspersed within polydiacetylene domains that function as the colour reporter. The optical detection scheme is based on visible blue-red transitions of polydiacetylene, induced by amphiphilic analytes interacting with the film.