Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Copper prevents amyloid-β(1-42) from forming amyloid fibrils under near-physiological conditions in vitro.

ABSTRACT: The aggregation and deposition of amyloid-β((1-42) )(Aβ(42)) in the brain is implicated in the aetiology of Alzheimer's disease (AD). While the mechanism underlying its deposition in vivo is unknown its precipitation in vitro is influenced by metal ions. For example, Aβ(42) is known to bind copper, Cu(II), in vitro and binding results in aggregation of the peptide. The biophysical properties of Cu(II)-Aβ(42) aggregates are of significant importance to their putative involvement in the amyloid cascade hypothesis of AD and are currently the subject of strong debate. In particular the question has been raised if sub- and super-stoichiometric concentrations of Cu(II) act in opposing ways in respectively accelerating and preventing amyloid fibril formation by Aβ(42). Herein we have used fluorimetry and transmission electron microscopy to provide unequivocal evidence that under near-physiological conditions both sub- and super-stoichiometric concentrations of Cu(II) prevented the assembly of Aβ(42) into ThT-positive β-sheet rich amyloid fibrils.

SUBMITTER: Mold M

PROVIDER: S-EPMC3570782 | biostudies-other | 2013

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Extreme extensibility of copper foil under compound forming conditions.

Project description:A copper foil with an extreme extensibility up to 43,684% was obtained without any intermediate annealing by means of asynchronous rolling with high tension. It was found that under the combination of compression, shearing and tension, the copper foil represents a wonderful phenomenon. As the reduction increases, the specimen hardness increases up to a peak value 138 HV0.05 when the foil thickness rolled to around 100??m, and then it decreases down to 78 HV0.05 when the foil thickness rolled to the final size 19??m. It tells us that the strain-softening effect occurs when the foil thickness is rolled down to a threshold level. The experimental results bring us some fresh ideas different with the traditional understanding on the strain-hardening mechanism of metals, which provides an experimental basis to establish the forming mechanism of the thin foil.

| S-EPMC6506452 | biostudies-literature

Formation of distinct prion protein amyloid fibrils under identical experimental conditions.

Project description:Protein aggregation into amyloid fibrils is linked to multiple neurodegenerative disorders, such as Alzheimer's, Parkinson's or Creutzfeldt-Jakob disease. A better understanding of the way these aggregates form is vital for the development of drugs. A large detriment to amyloid research is the ability of amyloidogenic proteins to spontaneously aggregate into multiple structurally distinct fibrils (strains) with different stability and seeding properties. In this work we show that prion proteins are capable of forming more than one type of fibril under the exact same conditions by assessing their Thioflavin T (ThT) binding ability, morphology, secondary structure, stability and seeding potential.

| S-EPMC7067779 | biostudies-literature

3D structure of Alzheimer's amyloid-beta(1-42) fibrils.

Project description:Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-beta (Abeta) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising Abeta(1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register beta-sheet arrangement from previous solid-state NMR studies. Although residues 1-17 are disordered, residues 18-42 form a beta-strand-turn-beta-strand motif that contains two intermolecular, parallel, in-register beta-sheets that are formed by residues 18-26 (beta1) and 31-42 (beta2). At least two molecules of Abeta(1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand beta1 of the nth molecule and the even-numbered residues of strand beta2 of the (n - 1)th molecule. This interaction pattern leads to partially unpaired beta-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of Abeta fibril growth. It also provides a structural basis for fibrillization inhibitors.

| S-EPMC1297669 | biostudies-literature

Key Residues for the Formation of A?42 Amyloid Fibrils.

Project description:Formation of amyloid fibrils by A?42 protein is a pathological hallmark of Alzheimer's disease. A?42 fibrillization is a nucleation-dependent polymerization process, in which nucleation is the rate-limiting step. Structural knowledge of the fibril nucleus is important to understand the molecular mechanism of A? aggregation and is also critical for successful modulation of the fibrillization process. Here, we used a scanning mutagenesis approach to study the role of each residue position in A?42 fibrillization kinetics. The side chain we used to replace the native residue is a nitroxide spin label called R1, which was introduced using site-directed spin labeling. In this systematic study, all residue positions of A?42 sequence were studied, and we identified six key residues for the A?42 fibril formation: H14, E22, D23, G33, G37, and G38. Our results suggest that charges at positions 22 and 23 and backbone flexibilities at positions 33, 37, and 38 play key roles in A?42 fibrillization kinetics. Our results also suggest that the formation of a ?-strand at residues 15-21 is an important feature in A?42 fibril nucleus. In overall evaluation of all of the mutational effects on fibrillization kinetics, we found that the thioflavin T fluorescence at the aggregation plateau is a poor indicator of aggregation rates.

| S-EPMC6068601 | biostudies-literature

High-Resolution Diffusion Measurements of Proteins by NMR under Near-Physiological Conditions.

Project description:Measuring the translational diffusion of proteins under physiological conditions can be very informative, especially when multiple diffusing species can be distinguished. Diffusion NMR or diffusion-ordered spectroscopy (DOSY) is widely used to study molecular diffusion, where protons are used as probes, which can be further edited by the proton-attached heteronuclei to provide additional resolution. For example, the combination of the backbone amide protons (1HN) to measure diffusion with the well-resolved 1H/15N correlations has afforded high-resolution DOSY experiments. However, significant amide-water proton exchange at physiological temperature and pH can affect the accuracy of diffusion data or cause complete loss of DOSY signals. Although aliphatic protons do not exchange with water protons, and thus are potential probes to measure diffusion rates, 1H/13C correlations are often in spectral overlap or masked by the water signal, which hampers the use of these correlations. In this report, a method was developed that separates the nuclei used for diffusion (α protons, 1Hα) and those used for detection (1H/15N and 13C'/15N correlations). This approach enables high-resolution diffusion measurements of polypeptides in a mixture of biomolecules, thereby providing a powerful tool to investigate coexisting species under physiologically relevant conditions.

| S-EPMC7431297 | biostudies-literature

Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils.

Project description:The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.

| S-EPMC2922021 | biostudies-literature

Amyloid formation by human carboxypeptidase D transthyretin-like domain under physiological conditions.

Project description:Protein aggregation is linked to a growing list of diseases, but it is also an intrinsic property of polypeptides, because the formation of functional globular proteins comes at the expense of an inherent aggregation propensity. Certain proteins can access aggregation-prone states from native-like conformations without the need to cross the energy barrier for unfolding. This is the case of transthyretin (TTR), a homotetrameric protein whose dissociation into its monomers initiates the aggregation cascade. Domains with structural homology to TTR exist in a number of proteins, including the M14B subfamily carboxypeptidases. We show here that the monomeric transthyretin-like domain of human carboxypeptidase D aggregates under close to physiological conditions into amyloid structures, with the population of folded but aggregation-prone states being controlled by the conformational stability of the domain. We thus confirm that the TTR fold keeps a generic residual aggregation propensity upon folding, resulting from the presence of preformed amyloidogenic ?-strands in the native state. These structural elements should serve for functional/structural purposes, because they have not been purged out by evolution, but at the same time they put proteins like carboxypeptidase D at risk of aggregation in biological environments and thus can potentially lead to deposition diseases.

| S-EPMC4256313 | biostudies-literature

Identifying the amylome, proteins capable of forming amyloid-like fibrils.

Project description:The amylome is the universe of proteins that are capable of forming amyloid-like fibrils. Here we investigate the factors that enable a protein to belong to the amylome. A major factor is the presence in the protein of a segment that can form a tightly complementary interface with an identical segment, which permits the formation of a steric zipper-two self-complementary beta sheets that form the spine of an amyloid fibril. Another factor is sufficient conformational freedom of the self-complementary segment to interact with other molecules. Using RNase A as a model system, we validate our fibrillogenic predictions by the 3D profile method based on the crystal structure of NNQQNY and demonstrate that a specific residue order is required for fiber formation. Our genome-wide analysis revealed that self-complementary segments are found in almost all proteins, yet not all proteins form amyloids. The implication is that chaperoning effects have evolved to constrain self-complementary segments from interaction with each other.

| S-EPMC2840437 | biostudies-literature

Mechanical measurement of hydrogen bonded host-guest systems under non-equilibrium, near-physiological conditions.

Project description:Decades after the birth of supramolecular chemistry, there are many techniques to measure noncovalent interactions, such as hydrogen bonding, under equilibrium conditions. As ensembles of molecules rapidly lose coherence, we cannot extrapolate bulk data to single-molecule events under non-equilibrium conditions, more relevant to the dynamics of biological systems. We present a new method that exploits the high force resolution of optical tweezers to measure at the single molecule level the mechanical strength of a hydrogen bonded host-guest pair out of equilibrium and under near-physiological conditions. We utilize a DNA reporter to unambiguously isolate single binding events. The Hamilton receptor-cyanuric acid host-guest system is used as a test bed. The force required to dissociate the host-guest system is ∼17 pN and increases with the pulling rate as expected for a system under non-equilibrium conditions. Blocking one of the hydrogen bonding sites results in a significant decrease of the force-to-break by 1-2 pN, pointing out the ability of the method to resolve subtle changes in the mechanical strength of the binding due to the individual H-bonding components. We believe the method will prove to be a versatile tool to address important questions in supramolecular chemistry.

| S-EPMC5625567 | biostudies-literature

Interprotofilament interactions between Alzheimer's Abeta1-42 peptides in amyloid fibrils revealed by cryoEM.

Project description:Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of amyloid plaques in the brain. This amyloid primarily contains amyloid-beta (Abeta), a 39- to 43-aa peptide derived from the proteolytic cleavage of the endogenous amyloid precursor protein. The 42-residue-length Abeta peptide (Abeta(1-42)), the most abundant Abeta peptide found in plaques, has a much greater propensity to self-aggregate into fibrils than the other peptides and is believed to be more pathogenic. Synthetic human Abeta(1-42) peptides self-aggregate into stable but poorly-ordered helical filaments. We determined their structure to approximately 10-A resolution by using cryoEM and the iterative real-space reconstruction method. This structure reveals 2 protofilaments winding around a hollow core. Previous hairpin-like NMR models for Abeta(17-42) fit well in the cryoEM density map and reveal that the juxtaposed protofilaments are joined via the N terminus of the peptide from 1 protofilament connecting to the loop region of the peptide in the opposite protofilament. This model of mature Abeta(1-42) fibrils is markedly different from previous cryoEM models of Abeta(1-40) fibrils. In our model, the C terminus of Abeta forms the inside wall of the hollow core, which is supported by partial proteolysis analysis.

| S-EPMC2660777 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data