Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pyroglutamylated amyloid-β peptide reverses cross β-sheets by a prion-like mechanism.

ABSTRACT: The amyloid hypothesis causatively relates the fibrillar deposits of amyloid β peptide (Aβ) to Alzheimer's disease (AD). More recent data, however, identify the soluble oligomers as the major cytotoxic entities. Pyroglutamylated Aβ (pE-Aβ) is present in AD brains and exerts augmented neurotoxicity, which is believed to result from its higher β-sheet propensity and faster fibrillization. While this concept is based on a set of experimental results, others have reported similar β-sheet contents in unmodified and pyroglutamylated Aβ, and slower aggregation of pE-Aβ as compared to unmodified Aβ, leaving the issue unresolved. Here, we assess the structural differences between Aβ and pE-Aβ peptides that may underlie their distinct cytotoxicities. Transmission electron microscopy identifies a larger number of prefibrillar aggregates of pE-Aβ at early stages of aggregation and suggests that pE-Aβ affects the fibrillogenesis even at low molar fractions. Circular dichroism and FTIR data indicate that while the unmodified Aβ readily forms β-sheet fibrils in aqueous media, pE-Aβ displays increased α-helical and decreased β-sheet propensity. Moreover, isotope-edited FTIR spectroscopy shows that pE-Aβ reverses β-sheet formation and hence fibrillogenesis of the unmodified Aβ peptide via a prion-like mechanism. These data provide a novel structural mechanism for pE-Aβ hypertoxicity; pE-Aβ undergoes faster formation of prefibrillar aggregates due to its increased hydrophobicity, thus shifting the initial stages of fibrillogenesis toward smaller, hypertoxic oligomers of partial α-helical structure.

SUBMITTER: Matos JO

PROVIDER: S-EPMC4216196 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

An amyloid-forming peptide from the yeast prion Sup35 reveals a dehydrated beta-sheet structure for amyloid.

Project description:X-ray diffraction and other biophysical tools reveal features of the atomic structure of an amyloid-like crystal. Sup35, a prion-like protein in yeast, forms fibrillar amyloid assemblies intrinsic to its prion function. We have identified a polar peptide from the N-terminal prion-determining domain of Sup35 that exhibits the amyloid properties of full-length Sup35, including cooperative kinetics of aggregation, fibril formation, binding of the dye Congo red, and the characteristic cross-beta x-ray diffraction pattern. Microcrystals of this peptide also share the principal properties of the fibrillar amyloid, including a highly stable, beta-sheet-rich structure and the binding of Congo red. The x-ray powder pattern of the microcrystals, extending to 0.9-A resolution, yields the unit cell dimensions of the well-ordered structure. These dimensions restrict possible atomic models of this amyloid-like structure and demonstrate that it forms packed, parallel-stranded beta-sheets. The unusually high density of the crystals shows that the packed beta-sheets are dehydrated, despite the polar character of the side chains. These results suggest that amyloid is a highly intermolecularly bonded, dehydrated array of densely packed beta-sheets. This dry beta-sheet could form as Sup35 partially unfolds to expose the peptide, permitting it to hydrogen-bond to the same peptide of other Sup35 molecules. The implication is that amyloid-forming units may be short segments of proteins, exposed for interactions by partial unfolding.

| S-EPMC30146 | biostudies-literature

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release.

Project description:Amyloid-β peptide (Aβ1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer's disease. Aβ1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) in immune cells within and out of the nervous system. Known interaction partners of Aβ1-42 are α7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Aβ1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1β by canonical and non-canonical agonists of nAChRs containing subunits α7, α9, and/or α10. Here, we tested the hypothesis that Aβ1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and Aβ1-42. IL-1β concentrations were measured in the supernatant. Aβ1-42 dose-dependently (IC50 = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1β-release by monocytic cells, whereas reverse Aβ42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Aβ1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Aβ1-42 in the context of sterile systemic inflammation.

| S-EPMC7564705 | biostudies-literature

A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein.

Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. One AD hallmark is the aggregation of β-amyloid (Aβ) into soluble oligomers and insoluble fibrils. Several studies have reported that oligomers rather than fibrils are the most toxic species in AD progression. Aβ oligomers bind with high affinity to membrane-associated prion protein (PrP), leading to toxic signaling across the cell membrane, which makes the Aβ-PrP interaction an attractive therapeutic target. Here, probing this interaction in more detail, we found that both full-length, soluble human (hu) PrP(23-230) and huPrP(23-144), lacking the globular C-terminal domain, bind to Aβ oligomers to form large complexes above the megadalton size range. Following purification by sucrose density-gradient ultracentrifugation, the Aβ and huPrP contents in these heteroassemblies were quantified by reversed-phase HPLC. The Aβ:PrP molar ratio in these assemblies exhibited some limited variation depending on the molar ratio of the initial mixture. Specifically, a molar ratio of about four Aβ to one huPrP in the presence of an excess of huPrP(23-230) or huPrP(23-144) suggested that four Aβ units are required to form one huPrP-binding site. Of note, an Aβ-binding all-d-enantiomeric peptide, RD2D3, competed with huPrP for Aβ oligomers and interfered with Aβ-PrP heteroassembly in a concentration-dependent manner. Our results highlight the importance of multivalent epitopes on Aβ oligomers for Aβ-PrP interactions and have yielded an all-d-peptide-based, therapeutically promising agent that competes with PrP for these interactions.

| S-EPMC6187637 | 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

Common molecular mechanism of amyloid pore formation by Alzheimer's β-amyloid peptide and α-synuclein.

Project description:Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein.

| S-EPMC4926208 | biostudies-literature

Membrane-Accelerated Amyloid-? Aggregation and Formation of Cross-? Sheets.

Project description:Amyloid- ? aggregates play a causative role in Alzheimer's disease. These aggregates are a product of the physical environment provided by the basic neuronal membrane, composed of a lipid bilayer. The intrinsic properties of the lipid bilayer allow amyloid- ? peptides to nucleate and form well-ordered cross- ? sheets within the membrane. Here, we correlate the aggregation of the hydrophobic fragment of the amyloid- ? protein, A ? 25 - 35 , with the hydrophobicity, fluidity, and charge density of a lipid bilayer. We summarize recent biophysical studies of model membranes and relate these to the process of aggregation in physiological systems.

| S-EPMC5618134 | biostudies-literature

Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase.

Project description:The membrane-embedded γ-secretase complex processively cleaves within the transmembrane domain of amyloid precursor protein (APP) to produce 37-to-43-residue amyloid β-peptides (Aβ) of Alzheimer's disease (AD). Despite its importance in pathogenesis, the mechanism of processive proteolysis by γ-secretase remains poorly understood. Here, mass spectrometry and Western blotting were used to quantify the efficiency of tripeptide trimming of wild-type (WT) and familial AD (FAD) mutant Aβ49. In comparison to WT Aβ49, the efficiency of tripeptide trimming was similar for the I45F, A42T, and V46F Aβ49 FAD mutants but substantially diminished for the I45T and T48P mutants. In parallel with biochemical experiments, all-atom simulations using a novel peptide Gaussian accelerated molecular dynamics (Pep-GaMD) method were applied to investigate the tripeptide trimming of Aβ49 by γ-secretase. The starting structure was the active γ-secretase bound to Aβ49 and APP intracellular domain (AICD), as generated from our previous study that captured the activation of γ-secretase for the initial endoproteolytic cleavage of APP (Bhattarai, A., ACS Cent. Sci. 2020, 6, 969-983). Pep-GaMD simulations captured remarkable structural rearrangements of both the enzyme and substrate, in which hydrogen-bonded catalytic aspartates and water became poised for tripeptide trimming of Aβ49 to Aβ46. These structural changes required a positively charged N-terminus of endoproteolytic coproduct AICD, which could dissociate during conformational rearrangements of the protease and Aβ49. The simulation findings were highly consistent with biochemical experimental data. Taken together, our complementary biochemical experiments and Pep-GaMD simulations have enabled elucidation of the mechanism of tripeptide trimming of Aβ49 by γ-secretase.

| S-EPMC9798850 | 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

The amphibian antimicrobial peptide uperin 3.5 is a cross-α/cross-β chameleon functional amyloid.

Project description:Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial PSMα3 cytotoxin. The fibrils of uperin 3.5 and PSMα3 comprised antiparallel and parallel helical sheets, respectively, recapitulating properties of β-sheets. Uperin 3.5 demonstrated chameleon properties of a secondary structure switch, forming mostly cross-β fibrils in the absence of lipids. Uperin 3.5 helical fibril formation was largely induced by, and formed on, bacterial cells or membrane mimetics, and led to membrane damage and cell death. These findings suggest a regulation mechanism, which includes storage of inactive peptides as well as environmentally induced activation of uperin 3.5, via chameleon cross-α/β amyloid fibrils.

| S-EPMC7826344 | biostudies-literature

Amyloid β-peptides 1-40 and 1-42 form oligomers with mixed β-sheets.

Project description:Two main amyloid-β peptides of different length (Aβ40 and Aβ42) are involved in Alzheimer's disease. Their relative abundance is decisive for the severity of the disease and mixed oligomers may contribute to the toxic species. However, little is know about the extent of mixing. To study whether Aβ40 and Aβ42 co-aggregate, we used Fourier transform infrared spectroscopy in combination with 13C-labeling and spectrum calculation and focused on the amide I vibration, which is sensitive to backbone structure. Mixtures of monomeric labeled Aβ40 and unlabeled Aβ42 (and vice versa) were co-incubated for ∼20 min and their infrared spectrum recorded. The position of the main 13C-amide I' band shifted to higher wavenumbers with increasing admixture of 12C-peptide due to the presence of 12C-amides in the vicinity of 13C-amides. The results indicate that Aβ40 and Aβ42 form mixed oligomers with a largely random distribution of Aβ40 and Aβ42 strands in their β-sheets. The structures of the mixed oligomers are intermediate between those of the pure oligomers. There is no indication that one of the peptides forces the backbone structure of its oligomers on the other peptide when they are mixed as monomers. We also demonstrate that isotope-edited infrared spectroscopy can distinguish aggregation modulators that integrate into the backbone structure of their interaction partner from those that do not. As an example for the latter case, the pro-inflammatory calcium binding protein S100A9 is shown not to incorporate into the β-sheets of Aβ42.

| S-EPMC5857929 | 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