Interaction of Aβ42 with Membranes Triggers the Self-Assembly into Oligomers.
Ontology highlight
ABSTRACT:
SUBMITTER: Banerjee S
PROVIDER: S-EPMC7036922 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Significant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer's and Parkinson's diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer's disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.
| S-EPMC7846799 | biostudies-literature
Project description:Bacterial photosynthetic membranes, also known as chromatophores, are tightly packed with integral membrane proteins that work together to carry out photosynthesis. Chromatophores display a wide range of cellular morphologies; spherical, tubular, and lamellar chromatophores have all been observed in different bacterial species, or with different protein constituents. Through recent computational modeling and simulation, it has been demonstrated that the light-harvesting complexes abundant in chromatophores induce local membrane curvature via multiple mechanisms. These protein complexes assemble to generate a global curvature and sculpt the chromatophores into various cellular-scale architectures.
| S-EPMC3086839 | biostudies-literature
Project description:The self-assembly of amyloid (Aβ) proteins into nano-aggregates is a hallmark of Alzheimer's disease (AD) development, yet the mechanism of how disordered monomers assemble into aggregates remains elusive. Here, we applied long-time molecular dynamics simulations to fully characterize the assembly of Aβ42 monomers into dimers. Monomers undergo conformational changes during their interaction, but the resulting dimer structures do not resemble those found in fibril structures. To identify natural conformations of dimers among a set of simulated ones, validation approaches were developed and applied, and a subset of dimer conformations were characterized. These dimers do not contain long β-strands that are usually found in fibrils. The dimers are stabilized primarily by interactions within the central hydrophobic regions and the C-terminal regions, with a contribution from local hydrogen bonding. The dimers are dynamic, as evidenced by the existence of a set of conformations and by the quantitative analyses of the dimer dissociation process.
| S-EPMC5114164 | biostudies-literature
Project description:A popular working hypothesis of Alzheimer's disease causation is amyloid β-protein oligomers are the key neuropathogenetic agents. Rigorously elucidating the role of oligomers requires the production of stable oligomers of each size. We previously used zero-length photochemical cross-linking to allow stabilization, isolation, and determination of structure-activity relationships of pure populations of Aβ40 dimers, trimers, and tetramers. We also attempted to study Aβ42 but found that Aβ42 oligomers subjected to the same procedures were not completely stable. On the basis of the fact that Tyr is a critical residue in cross-linking chemistry, we reasoned that the chemical accessibility of Tyr10 in Aβ42 must differ from that in Aβ40. We thus chemically synthesized four singly substituted Tyr variants that placed the Tyr in different positions across the Aβ42 sequence. We then studied the stability of the resulting cross-linked oligomers as well as procedures for fractionating the oligomers to obtain pure populations of different sizes. We found that [Phe(10),Tyr(42)]Aβ42 produced stable oligomers yielding highly pure populations of dimers through heptamers. This provides the means to establish formal structure-activity relationships of these important Aβ42 assemblies. In addition, we were able to analyze the dissociation patterns of non-cross-linked oligomers to produce a model for oligomer formation. This work is relevant to the determination of structure-activity relationships that have the potential to provide mechanistic insights into disease pathogenesis.
| S-EPMC5104494 | biostudies-literature
Project description:Aβ42 oligomers play key roles in the pathogenesis of Alzheimer disease, but their structures remain elusive partly due to their transient nature. Here, we show that Aβ42 in a fusion construct can be trapped in a stable oligomer state, which recapitulates characteristics of prefibrillar Aβ42 oligomers and enables us to establish their detailed structures. Site-directed spin labeling and electron paramagnetic resonance studies provide structural restraints in terms of side chain mobility and intermolecular distances at all 42 residue positions. Using these restraints and other biophysical data, we present a novel atomic-level oligomer model. In our model, each Aβ42 protein forms a single β-sheet with three β-strands in an antiparallel arrangement. Each β-sheet consists of four Aβ42 molecules in a head-to-tail arrangement. Four β-sheets are packed together in a face-to-back fashion. The stacking of identical segments between different β-sheets within an oligomer suggests that prefibrillar oligomers may interconvert with fibrils via strand rotation, wherein β-strands undergo an ∼90° rotation along the strand direction. This work provides insights into rational design of therapeutics targeting the process of interconversion between toxic oligomers and non-toxic fibrils.
| S-EPMC4175361 | biostudies-literature
Project description:In conformational disorders, it is not evident which amyloid aggregates affect specific molecular mechanisms or cellular pathways, which cause disease because of their quantity and mechanical features and which states in aggregate formation are pathogenic. Due to the increasing consensus that prefibrillar oligomers play a major role in conformational diseases, there is a growing interest in understanding the characteristics of metastable polypeptide associations.Here, we show that human latexin, a protein that shares the same fold with cystatin C, assembles into stable spherical amyloid-like oligomers that bind thioflavin-T and congo red similarly to common amyloid structures but do not evolve into fibrils. Latexin self-assembly correlates with the formation of a mostly denaturated state rather than with the population of partially structured intermediates during the unfolding process. The results suggest that unfolding of alpha-helix 3 might be involved in the transition of latexin toward amyloidotic species, supporting the notion of the protective role of the native protein structure against polymerization.Overall the data herein indicate that latexin could be a good model for the study of the structural and sequential determinants of oligomeric assemblies in protein aggregation processes.
| S-EPMC2212644 | biostudies-literature
Project description:In biological systems and nanoscale assemblies, the self-association of DNA is typically studied and applied in the context of the evolved or directed design of base sequences that give complementary pairing, duplex formation, and specific structural motifs. Here we consider the collective behavior of DNA solutions in the distinctly different regime where DNA base sequences are chosen at random or with varying degrees of randomness. We show that in solutions of completely random sequences, corresponding to a remarkably large number of different molecules, e.g., approximately 10(12) for random 20-mers, complementary still emerges and, for a narrow range of oligomer lengths, produces a subtle hierarchical sequence of structured self-assembly and organization into liquid crystal (LC) phases. This ordering follows from the kinetic arrest of oligomer association into long-lived partially paired double helices, followed by reversible association of these pairs into linear aggregates that in turn condense into LC domains.
| S-EPMC3268275 | biostudies-literature
Project description:Three evolutionarily conserved proteins known as SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors) mediate exocytosis from single cell eukaryotes to neurons. Among neuronal SNAREs, syntaxin and SNAP-25 (synaptosome-associated protein of 25 kDa) reside on the plasma membrane, whereas synaptobrevin resides on synaptic vesicles prior to fusion. The SNARE motifs of the three proteins form a helical bundle which probably drives membrane fusion. Since studies in vivo suggested an importance for multiple SNARE complexes in the fusion process, and models appeared in the literature with large numbers of SNARE bundles executing the fusion process, we analysed the quaternary structure of the full-length native SNARE complexes in detail. By employing a preparative immunoaffinity procedure we isolated all of the SNARE complexes from brain, and have shown by size-exclusion chromatography and negative stain electron microscopy that they exist as approx. 30 nm particles containing, most frequently, 3 or 4 bundles emanating from their centre. Using highly purified, individual, full-length SNAREs we demonstrated that the oligomerization of SNAREs into star-shaped particles with 3 to 4 bundles is an intrinsic property of these proteins and is not dependent on other proteins, as previously hypothesized. The average number of the SNARE bundles in the isolated fusion particles corresponds well with the co-operativity observed in calcium-triggered neuronal exocytosis.
| S-EPMC1186695 | biostudies-literature
Project description:Fluorinated alcohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) have the ability to promote α-helix and β-hairpin structure in proteins and peptides. HFIP has been used extensively to dissolve various amyloidogenic proteins and peptides including Aβ, in order to ensure their monomeric status. In this paper, we have investigated the self-assembly of Aβ40, Aβ42, and Aβ43 in aqueous mixtures of fluorinated alcohols from freshly dissolved stock solutions in HFIP. We have observed that formation of fibrillar and non-fibrillar structures are dependent on the solvent composition. Peptides form fibrils with ease when reconstituted in deionized water from freshly dissolved HFIP stocks. In aqueous mixtures of fluorinated alcohols, either predominant fibrillar structures or clustered aggregates were observed. Aqueous mixtures of 20% HFIP are more favourable for Aβ fibril formation as compared to 20% TFE. When Aβ40, Aβ42, and Aβ43 stocks in HFIP are diluted in 50% aqueous mixtures in phosphate buffer or deionized water followed by slow evaporation of HFIP, Aβ peptides form fibrils in phosphate buffer and deionized water. The clustered structures could be off-pathway aggregates. Aβ40, Aβ42, and Aβ43 showed significant α-helical content in freshly dissolved HFIP stocks. The α-helical conformational intermediate in Aβ40, Aβ42, and Aβ43 could favour the formation of both fibrillar and non-fibrillar aggregates depending on solvent conditions and rate of α-helical to β-sheet transition.
| S-EPMC4550328 | biostudies-literature
Project description:The β-amyloid (Aβ) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a β-hairpin stabilized variant of Aβ42 that results from an intramolecular disulphide bridge (A21C/A31C; Aβ42cc), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second β-strand have been demonstrated to bind to Aβ42cc, lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type Aβ42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop Aβ antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD.
| S-EPMC4243997 | biostudies-literature