Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Coassembly of enantiomeric amphipathic peptides into amyloid-inspired rippled ?-sheet fibrils.

ABSTRACT: Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids self-assemble into amyloid-inspired, ?-sheet nanoribbon fibrils. Herein, we report a new fibril type that is formed from equimolar mixtures of enantiomeric amphipathic peptides (L- and D-(FKFE)(2)). Spectroscopic analysis indicates that these peptides do not self-sort and assemble into enantiomeric fibrils composed of all-l and all-d peptides, but rather coassemble into fibrils that contain alternating L- and D-peptides in a "rippled ?-sheet" orientation. Isothermal titration calorimetry indicates an enthalpic advantage for rippled ?-sheet coassembly compared to self-sorted ?-sheet assembly of enantiomeric peptides.

SUBMITTER: Swanekamp RJ

PROVIDER: S-EPMC7316157 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Coassembly of enantiomeric amphipathic peptides into amyloid-inspired rippled β-sheet fibrils.

Swanekamp Ria J RJ DiMaio John T M JT Bowerman Charles J CJ Nilsson Bradley L BL

Journal of the American Chemical Society 20120316 12

Amphipathic peptides composed of alternating hydrophobic and hydrophilic amino acids self-assemble into amyloid-inspired, β-sheet nanoribbon fibrils. Herein, we report a new fibril type that is formed from equimolar mixtures of enantiomeric amphipathic peptides (L- and D-(FKFE)(2)). Spectroscopic analysis indicates that these peptides do not self-sort and assemble into enantiomeric fibrils composed of all-l and all-d peptides, but rather coassemble into fibrils that contain alternating L- and D- ...[more]

PMID: 22420540

Similar Datasets

Rippled ?-Sheet Formation by an Amyloid-? Fragment Indicates Expanded Scope of Sequence Space for Enantiomeric ?-Sheet Peptide Coassembly.

Project description:In 1953, Pauling and Corey predicted that enantiomeric ?-sheet peptides would coassemble into so-called "rippled" ?-sheets, in which the ?-sheets would consist of alternating l- and d-peptides. To date, this phenomenon has been investigated primarily with amphipathic peptide sequences composed of alternating hydrophilic and hydrophobic amino acid residues. Here, we show that enantiomers of a fragment of the amyloid-? (A?) peptide that does not follow this sequence pattern, amyloid-? (16-22), readily coassembles into rippled ?-sheets. Equimolar mixtures of enantiomeric amyloid-? (16-22) peptides assemble into supramolecular structures that exhibit distinct morphologies from those observed by self-assembly of the single enantiomer pleated ?-sheet fibrils. Formation of rippled ?-sheets composed of alternating l- and d-amyloid-? (16-22) is confirmed by isotope-edited infrared spectroscopy and solid-state NMR spectroscopy. Sedimentation analysis reveals that rippled ?-sheet formation by l- and d-amyloid-? (16-22) is energetically favorable relative to self-assembly into corresponding pleated ?-sheets. This work illustrates that coassembly of enantiomeric ?-sheet peptides into rippled ?-sheets is not limited to peptides with alternating hydrophobic/hydrophilic sequence patterns, but that a broader range of sequence space is available for the design and preparation of rippled ?-sheet materials.

| S-EPMC6571685 | biostudies-literature

Coassembly of Peptides Derived from ?-Sheet Regions of ?-Amyloid.

Project description:In this paper, we investigate the coassembly of peptides derived from the central and C-terminal regions of the ?-amyloid peptide (A?). In the preceding paper, J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b06000 , we established that peptides containing residues 17-23 (LVFFAED) from the central region of A? and residues 30-36 (AIIGLMV) from the C-terminal region of A? assemble to form homotetramers consisting of two hydrogen-bonded dimers. Here, we mix these tetramer-forming peptides and determine how they coassemble. Incorporation of a single 15N isotopic label into each peptide provides a spectroscopic probe with which to elucidate the coassembly of the peptides by 1H,15N HSQC. Job's method of continuous variation and nonlinear least-squares fitting reveal that the peptides form a mixture of heterotetramers in 3:1, 2:2, and 1:3 stoichiometries, in addition to the homotetramers. These studies also establish the relative stability of each tetramer and show that the 2:2 heterotetramer predominates. 15N-Edited NOESY shows the 2:2 heterotetramer comprises two different homodimers, rather than two heterodimers. The peptides within the heterotetramer segregate in forming the homodimer subunits, but the two homodimers coassemble in forming the heterotetramer. These studies show that the central and C-terminal regions of A? can preferentially segregate within ?-sheets and that the resulting segregated ?-sheets can further coassemble.

| S-EPMC5089069 | biostudies-literature

Spectroscopic Signature for Stable ?-Amyloid Fibrils versus ?-Sheet-Rich Oligomers.

Project description:We use two-dimensional IR (2D IR) spectroscopy to explore fibril formation for the two predominant isoforms of the ?-amyloid (A?1-40 and A?1-42) protein associated with Alzheimer's disease. Two-dimensional IR spectra resolve a transition at 1610 cm-1 in A? fibrils that does not appear in other A? aggregates, even those with predominantly ?-sheet-structure-like oligomers. This transition is not resolved in linear IR spectroscopy because it lies under the broad band centered at 1625 cm-1, which is the traditional infrared signature for amyloid fibrils. The feature is prominent in 2D IR spectra because 2D lineshapes are narrower and scale nonlinearly with transition dipole strengths. Transmission electron microscopy measurements demonstrate that the 1610 cm-1 band is a positive identification of amyloid fibrils. Sodium dodecyl sulfate micelles that solubilize and disaggregate preaggregated A? samples deplete the 1625 cm-1 band but do not affect the 1610 cm-1 band, demonstrating that the 1610 cm-1 band is due to very stable fibrils. We demonstrate that the 1610 cm-1 transition arises from amide I modes by mutating out the only side-chain residue that could give rise to this transition, and we explore the potential structural origins of the transition by simulating 2D IR spectra based on A? crystal structures. It was not previously possible to distinguish stable A? fibrils from the less stable ?-sheet-rich oligomers with infrared light. This 2D IR signature will be useful for Alzheimer's research on A? aggregation, fibril formation, and toxicity.

| S-EPMC5969533 | biostudies-literature

Antiparallel β-sheet architecture in Iowa-mutant β-amyloid fibrils.

Project description:Wild-type, full-length (40- and 42-residue) amyloid β-peptide (Aβ) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-β structures in which the β-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue Aβ (D23N-Aβ(1-40)), which is associated with early onset neurodegeneration, indicate that D23N-Aβ(1-40) fibrils can contain either parallel or antiparallel β-sheets. We report a protocol for producing structurally pure antiparallel D23N-Aβ(1-40) fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-Aβ(1-40) fibril structure. This model reveals how both parallel and antiparallel cross-β structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-Aβ(1-40) fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-Aβ(1-40) fibrils are cytotoxic. Thus, our antiparallel D23N-Aβ(1-40) fibril model represents a specific "toxic intermediate" in the aggregation process of a disease-associated Aβ mutant.

| S-EPMC3311365 | biostudies-literature

Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.

Project description:The amyloid-forming proteins tau, ?B crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein ?B crystallin (HspB5) and from amyloid ? fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid ? A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

| S-EPMC3684024 | biostudies-literature

Bicine promotes rapid formation of β-sheet-rich amyloid-β fibrils.

Project description:Fibrillar aggregates of amyloid-β (Aβ) are the main component of plaques lining the cerebrovasculature in cerebral amyloid angiopathy. As the predominant Aβ isoform in vascular deposits, Aβ40 is a valuable target in cerebral amyloid angiopathy research. However, the slow process of Aβ40 aggregation in vitro is a bottleneck in the search for Aβ-targeting molecules. In this study, we sought a method to accelerate the aggregation of Aβ40 in vitro, to improve experimental screening procedures. We evaluated the aggregating ability of bicine, a biological buffer, using various in vitro methods. Our data suggest that bicine promotes the aggregation of Aβ40 with high speed and reproducibility, yielding a mixture of aggregates with significant β-sheet-rich fibril formation and toxicity.

| S-EPMC7553346 | biostudies-literature

Topomimetics of amphipathic beta-sheet and helix-forming bactericidal peptides neutralize lipopolysaccharide endotoxins.

Project description:Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and beta-sheet-forming betapep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of nonpeptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10-8 M range, making them as effective as bactericidal/permeability increasing protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.

| S-EPMC4242098 | biostudies-literature

TANGO-Inspired Design of Anti-Amyloid Cyclic Peptides.

Project description:?-Amyloid peptide (A?) self-associates into oligomers and fibrils, in a process that is believed to directly lead to neuronal death in Alzheimer's disease. Compounds that bind to A?, and inhibit fibrillogenesis and neurotoxicity, are of interest as an anti-Alzheimer therapeutic strategy. Peptides are particularly attractive for this purpose, because they have advantages over small molecules in their ability to disrupt protein-protein interactions, yet they are amenable to tuning of their properties through chemical means, unlike antibodies. Self-complementation and peptide library screening are two strategies that have been employed in the search for peptides that bind to A?. We have taken a different approach, by designing A?-binding peptides using transthyretin (TTR) as a template. Previously, we demonstrated that a cyclic peptide, with sequence derived from the known A?-binding site on TTR, suppressed A? aggregation into fibrils and protected neurons against A? toxicity. Here, we searched for cyclic peptides with improved efficacy, by employing the algorithm TANGO, designed originally to identify amyloidogenic sequences in proteins. By using TANGO as a guide to predict the effect of sequence modifications on conformation and aggregation, we synthesized a significantly improved cyclic peptide. We demonstrate that the peptide, in binding to A?, redirects A? toward protease-sensitive, nonfibrillar aggregates. Cyclic peptides designed using this strategy have attractive solubility, specificity, and stability characteristics.

| S-EPMC5051546 | biostudies-literature

Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

Project description:Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

| S-EPMC2910621 | biostudies-literature

FTIR reveals structural differences between native beta-sheet proteins and amyloid fibrils.

Project description:The presence of beta-sheets in the core of amyloid fibrils raised questions as to whether or not beta-sheet-containing proteins, such as transthyretin, are predisposed to form such fibrils. However, we show here that the molecular structure of amyloid fibrils differs more generally from the beta-sheets in native proteins. This difference is evident from the amide I region of the infrared spectrum and relates to the distribution of the phi/psi dihedral angles within the Ramachandran plot, the average number of strands per sheet, and possibly, the beta-sheet twist. These data imply that amyloid fibril formation from native beta-sheet proteins can involve a substantial structural reorganization.

| S-EPMC2287307 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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