Dataset Information

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid ? Assemblies.

ABSTRACT: Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid ? (A?) oligomers in the brain of patients. Two principal variants of A? exist in humans: A?1-40 and A?1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of A?1-40 peptides can only assume U-shaped conformations while A?1-42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped A?17-42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.

SUBMITTER: Grasso G

PROVIDER: S-EPMC5855793 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

Grasso Gianvito G Rebella Martina M Muscat Stefano S Morbiducci Umberto U Tuszynski Jack J Danani Andrea A Deriu Marco A MA

International journal of molecular sciences 20180214 2

Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1-40 and Aβ1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1-40 peptides can only assume U-shaped conformations while Aβ1-42 can als ...[more]

PMID: 29443891

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Project description:Hibernators dramatically lower metabolism to save energy while fasting for months. Prolonged fasting challenges metabolic homeostasis, yet small-bodied hibernators emerge each spring ready to resume all aspects of active life, including immediate reproduction. The liver is the body’s metabolic hub, processing and detoxifying macromolecules to provide essential fuels to brain, muscle and other organs throughout the body. Here we quantify changes in liver gene expression across several distinct physiological states of hibernation in 13-lined ground squirrels, using RNA-seq to measure the steady-state transcriptome and GRO-seq to measure transcription for the first time in a hibernator. Our data capture key timepoints in both the seasonal and torpor-arousal cycles of hibernation. Strong positive correlation between transcription and the transcriptome indicates that transcriptional control dominates the known seasonal reprogramming of metabolic gene expression in liver for hibernation. During the torpor-arousal cycle, however, discordance develops between transcription and the steady-state transcriptome by at least two mechanisms: 1) although not transcribed during torpor, some transcripts are unusually stable across the torpor bout; and 2) unexpectedly, on some genes, we document continuing, slow elongation with a failure to terminate transcription across the torpor bout. While the steady-state RNAs corresponding to these readthrough transcripts did not increase during torpor, they did increase shortly after rewarming despite their simultaneously low transcription. Both of these mechanisms would assure the immediate availability of functional transcripts upon rewarming. Integration of transcriptional, post-transcriptional and RNA stability control mechanisms, all demonstrated in these data, likely initiate a serial gene expression program across the short euthermic period that restores the tissue and prepares the animal for the next bout of torpor.

Dataset Information

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid ? Assemblies.

Publications

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

Similar Datasets

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