Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Amyloid-β fibrils assembled on ganglioside-enriched membranes contain both parallel β-sheets and turns.

ABSTRACT: Some protein and peptide aggregates, such as those of amyloid-β protein (Aβ), are neurotoxic and have been implicated in several neurodegenerative diseases. Aβ accumulates at nanoclusters enriched in neuronal lipids called gangliosides in the presynaptic neuronal membrane, and the resulting oligomeric and/or fibrous forms accelerate the development of Alzheimer's disease. Although the presence of Aβ deposits at such nanoclusters is known, the mechanism of their assembly and the relationship between Aβ secondary structure and topography are still unclear. Here, we first confirmed by atomic force microscopy that Aβ₄₀ fibrils can be obtained by incubating seed-free Aβ₄₀ monomers with a membrane composed of sphingomyelin, cholesterol, and the ganglioside GM1. Using Fourier transform infrared (FTIR) reflection-absorption spectroscopy, we then found that these lipid-associated fibrils contained parallel β-sheets, whereas self-assembled Aβ₄₀ molecules formed antiparallel β-sheets. We also found that the fibrils obtained at GM1-rich nanoclusters were generated from turn Aβ₄₀ Our findings indicate that Aβ generally self-assembles into antiparallel β-structures but can also form protofibrils with parallel β-sheets by interacting with ganglioside-bound Aβ. We concluded that by promoting the formation of parallel β-sheets, highly ganglioside-enriched nanoclusters help accelerate the elongation of Aβ fibrils. These results advance our understanding of ganglioside-induced Aβ fibril formation in neuronal membranes and may help inform the development of additional therapies for Alzheimer's disease.

SUBMITTER: Matsubara T

PROVIDER: S-EPMC6130953 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

C-Terminal Truncated α-Synuclein Fibrils Contain Strongly Twisted β-Sheets.

Project description:C-terminal truncations of monomeric wild-type alpha-synuclein (henceforth WT-αS) have been shown to enhance the formation of amyloid aggregates both in vivo and in vitro and have been associated with accelerated progression of Parkinson's disease (PD). The correlation with PD may not solely be a result of faster aggregation, but also of which fibril polymorphs are preferentially formed when the C-terminal residues are deleted. Considering that different polymorphs are known to result in distinct pathologies, it is important to understand how these truncations affect the organization of αS into fibrils. Here we present high-resolution microscopy and advanced vibrational spectroscopy studies that indicate that the C-terminal truncation variant of αS, lacking residues 109-140 (henceforth referred to as 1-108-αS), forms amyloid fibrils with a distinct structure and morphology. The 1-108-αS fibrils have a unique negative circular dichroism band at ∼230 nm, a feature that differs from the canonical ∼218 nm band usually observed for amyloid fibrils. We show evidence that 1-108-αS fibrils consist of strongly twisted β-sheets with an increased inter-β-sheet distance and a higher solvent exposure than WT-αS fibrils, which is also indicated by the pronounced differences in the 1D-IR (FTIR), 2D-IR, and vibrational circular dichroism spectra. As a result of their distinct β-sheet structure, 1-108-αS fibrils resist incorporation of WT-αS monomers.

| S-EPMC5668890 | biostudies-literature

Structure and dynamics of parallel beta-sheets, hydrophobic core, and loops in Alzheimer's A beta fibrils.

Project description:We explore the relative contributions of different structural elements to the stability of Abeta fibrils by molecular-dynamics simulations performed over a broad range of temperatures (298 K to 398 K). Our fibril structures are based on solid-state nuclear magnetic resonance experiments of Abeta(1-40) peptides, with sheets of parallel beta-strands connected by loops and stabilized by interior salt bridges. We consider models with different interpeptide interfaces, and different staggering of the N- and C-terminal beta-strands along the fibril axis. Multiple 10-20 ns molecular-dynamics simulations show that fibril segments with 12 peptides are stable at ambient temperature. The different models converge toward an interdigitated side-chain packing, and present water channels solvating the interior D23/K28 salt bridges. At elevated temperatures, we observe the early phases of fibril dissociation as a loss of order in the hydrophilic loops connecting the two beta-strands, and in the solvent-exposed N-terminal beta-sheets. As the most dramatic structural change, we observe collective sliding of the N- and C-terminal beta-sheets on top of each other. The interior C-terminal beta-sheets in the hydrophobic core remain largely intact, indicating that their formation and stability is crucial to the dissociation/elongation and stability of Abeta fibrils.

| S-EPMC1852365 | biostudies-literature

Disulfide-Mediated β-Strand Dimers: Hyperstable β-Sheets Lacking Tertiary Interactions and Turns.

Project description:Disulfide bonds between cysteine residues are essential to the structure and folding of many proteins. Yet their role in the design of structured peptides and proteins has frequently been limited to use as intrachain covalent staples that reinforce existing structure or induce knot-like conformations. In β-hairpins, their placement at non-H-bonding positions across antiparallel strands has proven useful for achieving fully folded positive controls. Here we report a new class of designed β-sheet peptide dimers with strand-central disulfides as a key element. We have found that the mere presence of a disulfide bond near the middle of a short peptide chain is sufficient to nucleate some antiparallel β-sheet structure; addition of β-capping units and other favorable cross-strand interactions yield hyperstable sheets. Strand-central cystines were found to be superior to the best designed reversing turns in terms of nucleating β-sheet structure formation. We have explored the limitations and possibilities of this technique (the use of disulfides as sheet nucleators), and we provide a set of rules and rationales for the application and further design of disulfide-tethered "turnless" β-sheets.

| S-EPMC7450586 | biostudies-literature

Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p.

Project description:We report the results of solid-state nuclear magnetic resonance (NMR) and atomic force microscopy measurements on amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p (Ure2p(10)(-)(39)). Measurements of intermolecular (13)C-(13)C nuclear magnetic dipole-dipole couplings indicate that Ure2p(10)(-)(39) fibrils contain in-register parallel beta-sheets. Measurements of intermolecular (15)N-(13)C dipole-dipole couplings, using a new solid-state NMR technique called DSQ-REDOR, are consistent with hydrogen bonds between side chain amide groups of Gln18 residues. Such side chain hydrogen bonding interactions have been called "polar zippers" by M. F. Perutz and have been proposed to stabilize amyloid fibrils formed by peptides with glutamine- and asparagine-rich sequences, such as Ure2p(10)(-)(39). We propose that polar zipper interactions account for the in-register parallel beta-sheet structure in Ure2p(10)(-)(39) fibrils and that similar peptides will also exhibit parallel beta-sheet structures in amyloid fibrils. We present molecular models for Ure2p(10)(-)(39) fibrils that are consistent with available experimental data. Finally, we show that solid-state (13)C NMR chemical shifts for (13)C-labeled Ure2p(10)(-)(39) fibrils are insensitive to hydration level, indicating that the fibril structure is not affected by the presence or absence of bulk water.

| S-EPMC1380259 | biostudies-literature

Structure-Property Relationship Study of <i>N</i>-(Hydroxy)Peptides for the Design of Self-Assembled Parallel β-Sheets.

Project description:The design of novel and functional biomimetic foldamers remains a major challenge in creating mimics of native protein structures. Herein, we report the stabilization of a remarkably short β-sheet by incorporating N-(hydroxy)glycine (Hyg) residues into the backbone of peptides. These peptide-peptoid hybrids form unique parallel β-sheet structures by self-assembly upon hydrogenation. Our spectroscopic and crystallographic data suggest that the local conformational perturbations induced by N-(hydroxy)amides are outweighed by a network of strong interstrand hydrogen bonds.

| S-EPMC7659681 | biostudies-literature

2D Nano-Mica Sheets Assembled Membranes for High-Efficiency Oil/Water Separation.

Project description:Oil-polluted water has become one of the most important environmental concerns nowadays due to the increasing industrial oily wastewater and frequent oil spill accidents. Herein, a novel two-dimensional (2D) nano-mica sheets assembled composite membrane with underwater super-oleophobic properties was developed for effective oil/water separation. A 2D nano-mica sheet was synthesized by a facile solvent-assisted ultrasonic exfoliation and then the obtained 2D nano-mica sheets were co-deposited with dopamine on polyvinylidene fluoride substrate to prepare nano-mica composite membranes (NCM). The NCM is hydrophilic in air and super-oleophobic underwater (the water contact angle in the air is 37.6°, and the oil contact angle in water is 151.4°). Furthermore, the prepared NCM provided outstanding stability in different acid-base environments (pH = 1-11). Noteworthily, the oil removal rate is higher than 99.5% as the sodium dodecyl sulfate SDS-stabilized oil (soya-bean oil, mineral oil and pump oil) -in-water emulsions. Meanwhile, the NCM showed excellent reusability, as the oil removal efficiency kept at 99.0% after ten soya-bean oil-in-water or mineral oil-in-water emulsion filtration cycles. The present work paved a new way for developing a low-cost and environmentally friendly strategy for oily wastewater treatment and developed a high-increment utilization application field for natural minerals.

| S-EPMC9457926 | biostudies-literature

Conversion between parallel and antiparallel ?-sheets in wild-type and Iowa mutant A?40 fibrils.

Project description:Using a variant of Hamilton-replica-exchange, we study for wild type and Iowa mutant A?40 the conversion between fibrils with antiparallel ?-sheets and such with parallel ?-sheets. We show that wild type and mutant form distinct salt bridges that in turn stabilize different fibril organizations. The conversion between the two fibril forms leads to the release of small aggregates that in the Iowa mutant may shift the equilibrium from fibrils to more toxic oligomers.

| S-EPMC5785298 | biostudies-literature

The folding of acetyl(Ala)28NH2 and acetyl(Ala)40NH2 extended strand peptides into antiparallel β-sheets. A density functional theory study of β-sheets with β-turns.

Project description:We report ONIOM calculations using B3LYP/D95** and AM1 on β-sheet formation from acetyl(Ala)(N)NH(2) (N = 28 or 40). The sheets contain from one to four β-turns for N = 28 and up to six for N = 40. We have obtained four types of geometrically optimized structures. All contain only β-turns. They differ from each other in the types of β-turns formed. The unsolvated sheets containing two turns are most stable. Aqueous solvation (using the SM5.2 and CPCM methods) reduces the stabilities of the folded structures compared to the extended strands.

| S-EPMC3529134 | biostudies-literature

Out-of-Register Parallel β-Sheets and Antiparallel β-Sheets Coexist in 150-kDa Oligomers Formed by Amyloid-β(1-42).

Project description:We present solid-state NMR measurements of β-strand secondary structure and inter-strand organization within a 150-kDa oligomeric aggregate of the 42-residue variant of the Alzheimer's amyloid-β peptide (Aβ(1-42)). We build upon our previous report of a β-strand spanned by residues 30-42, which arranges into an antiparallel β-sheet. New results presented here indicate that there is a second β-strand formed by residues 11-24. Contrary to expectations, NMR data indicate that this second β-strand is organized into a parallel β-sheet despite the co-existence of an antiparallel β-sheet in the same structure. In addition, the in-register parallel β-sheet commonly observed for amyloid fibril structure does not apply to residues 11-24 in the 150-kDa oligomer. Rather, we present evidence for an inter-strand registry shift of three residues that likely alternate in direction between adjacent molecules along the β-sheet. We corroborated this unexpected scheme for β-strand organization using multiple two-dimensional NMR and 13C-13C dipolar recoupling experiments. Our findings indicate a previously unknown assembly pathway and inspire a suggestion as to why this aggregate does not grow to larger sizes.

| S-EPMC7387221 | biostudies-literature

Ultrathin self-assembled fibrin sheets.

Project description:Fibrin polymerizes into the fibrous network that is the major structural component of blood clots and thrombi. We demonstrate that fibrin from three different species can also spontaneously polymerize into extensive, molecularly thin, 2D sheets. Sheet assembly occurs in physiologic buffers on both hydrophobic and hydrophilic surfaces, but is routinely observed only when polymerized using very low concentrations of fibrinogen and thrombin. Sheets may have been missed in previous studies because they may be very short-lived at higher concentrations of fibrinogen and thrombin, and their thinness makes them very difficult to detect. We were able to distinguish fluorescently labeled fibrin sheets by polymerizing fibrin onto micro-patterned structured surfaces that suspended polymers 10 microm above and parallel to the cover-glass surface. We used a combined fluorescence/atomic force microscope system to determine that sheets were approximately 5 nm thick, flat, elastic and mechanically continuous. Video microscopy of assembling sheets showed that they could polymerize across 25-microm channels at hundreds of microm(2)/sec (approximately 10(13) subunits/s x M), an apparent rate constant many times greater than those of other protein polymers. Structural transitions from sheets to fibers were observed by fluorescence, transmission, and scanning electron microscopy. Sheets appeared to fold and roll up into larger fibers, and also to develop oval holes to form fiber networks that were "pre-attached" to the substrate and other fibers. We propose a model of fiber formation from sheets and compare it with current models of end-wise polymerization from protofibrils. Sheets could be an unanticipated factor in clot formation and adhesion in vivo, and are a unique material in their own right.

| S-EPMC2614779 | 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