Dataset Information

Fibrils of Truncated Pyroglutamyl-Modified A? Peptide Exhibit a Similar Structure as Wildtype Mature A? Fibrils.

ABSTRACT: Fibrillation of differently modified amyloid ? peptides and deposition as senile plaques are hallmarks of Alzheimer's disease. N-terminally truncated variants, where the glutamate residue 3 is converted into cyclic pyroglutamate (pGlu), form particularly toxic aggregates. We compare the molecular structure and dynamics of fibrils grown from wildtype A?(1-40) and pGlu3-A?(3-40) on the single amino acid level. Thioflavin T fluorescence, electron microscopy, and X-ray diffraction reveal the general morphology of the amyloid fibrils. We found good agreement between the (13)C and (15)N NMR chemical shifts indicative for a similar secondary structure of both fibrils. A well-known interresidual contact between the two ?-strands of the A? fibrils could be confirmed by the detection of interresidual cross peaks in a (13)C-(13)C NMR correlation spectrum between the side chains of Phe 19 and Leu 34. Small differences in the molecular dynamics of residues in the proximity to the pyroglutamyl-modified N-terminus were observed as measured by DIPSHIFT order parameter experiments.

SUBMITTER: Scheidt HA

PROVIDER: S-EPMC5030707 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fibrils of Truncated Pyroglutamyl-Modified Aβ Peptide Exhibit a Similar Structure as Wildtype Mature Aβ Fibrils.

Scheidt Holger A HA Adler Juliane J Krueger Martin M Huster Daniel D

Scientific reports 20160921

Fibrillation of differently modified amyloid β peptides and deposition as senile plaques are hallmarks of Alzheimer's disease. N-terminally truncated variants, where the glutamate residue 3 is converted into cyclic pyroglutamate (pGlu), form particularly toxic aggregates. We compare the molecular structure and dynamics of fibrils grown from wildtype Aβ(1-40) and pGlu3-Aβ(3-40) on the single amino acid level. Thioflavin T fluorescence, electron microscopy, and X-ray diffraction reveal the general ...[more]

PMID: 27650059

Similar Datasets

Project description:Alzheimer's disease is characterized by neuritic plaques, the main protein components of which are β-amyloid (Aβ) peptides deposited as β-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aβ peptides; it usually accompanies Alzheimer's disease, though it sometimes occurs in the absence of neuritic plaques, as AD also occurs without accompanying CAA. Although neuritic plaques and vascular deposits have similar protein compositions, one of the characteristic features of amyloids is polymorphism, i.e., the ability of a single pure peptide to adopt multiple conformations in fibrils, depending on fibrillization conditions. For this reason, we asked whether the Aβ fibrils in neuritic plaques differed structurally from those in cerebral blood vessels. To address this question, we used seeding techniques, starting with amyloid-enriched material from either brain parenchyma or cerebral blood vessels (using meninges as the source). These amyloid-enriched preparations were then added to fresh, disaggregated solutions of Aβ to make replicate fibrils, as described elsewhere. Such fibrils were then studied by solid-state NMR, fiber X-ray diffraction, and other biophysical techniques. We observed chemical shift differences between parenchymal vs. vascular-seeded replicate fibrils in select sites (in particular, Ala2, Phe4, Val12, and Gln15 side chains) in two-dimensional 13C-13C correlation solid-state NMR spectra, strongly indicating structural differences at these sites. X-ray diffraction studies also indicated that vascular-seeded fibrils displayed greater order than parenchyma-seeded fibrils in the "side-chain dimension" (~ 10 Å reflection), though the "hydrogen-bond dimensions" (~ 5 Å reflection) were alike. These results indicate that the different nucleation conditions at two sites in the brain, parenchyma and blood vessels, affect the fibril products that get formed at each site, possibly leading to distinct pathophysiological outcomes.

Dataset Information

Fibrils of Truncated Pyroglutamyl-Modified A? Peptide Exhibit a Similar Structure as Wildtype Mature A? Fibrils.

Publications

Fibrils of Truncated Pyroglutamyl-Modified Aβ Peptide Exhibit a Similar Structure as Wildtype Mature Aβ Fibrils.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets