Dataset Information

αB-Crystallin Chaperone Inhibits Aβ Aggregation by Capping the β-Sheet-Rich Oligomers and Fibrils.

ABSTRACT: Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB-crystallin (αBC) against Aβ fibrillization using discrete molecular dynamics simulations. Our computational results recapitulated the experimentally observed Aβ binding sites in αBC and suggested that αBC could bind to various Aβ aggregate species during the aggregation process-including monomers, dimers, and likely other high molecular weight oligomers, protofibrils, and fibrils-by capping the exposed β-sheet elongation surfaces. Thus, the nucleation of Aβ oligomers into fibrils and the fibril growth could be inhibited. Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic protein in degenerative diseases.

SUBMITTER: Sun Y

PROVIDER: S-EPMC7666094 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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αB-Crystallin Chaperone Inhibits Aβ Aggregation by Capping the β-Sheet-Rich Oligomers and Fibrils.

Sun Yunxiang Y Ding Feng F

The journal of physical chemistry. B 20201029 45

Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB-crystallin (αBC) against Aβ fibrillization using discrete molecular dynamics simulations. Our computational results recapitulated the experimentally observed Aβ binding sites in αBC and suggested tha ...[more]

PMID: 33119314

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Project description:The formation of β-sheet rich prion oligomers and fibrils from native prion protein (PrP) is thought to be a key step in the development of prion diseases. Many methods are available to convert recombinant prion protein into β-sheet rich fibrils using various chemical denaturants (urea, SDS, GdnHCl), high temperature, phospholipids, or mildly acidic conditions (pH 4). Many of these methods also require shaking or another form of agitation to complete the conversion process. We have identified that shaking alone causes the conversion of recombinant PrP to β-sheet rich oligomers and fibrils at near physiological pH (pH 5.5 to pH 6.2) and temperature. This conversion does not require any denaturant, detergent, or any other chemical cofactor. Interestingly, this conversion does not occur when the water-air interface is eliminated in the shaken sample. We have analyzed shaking-induced conversion using circular dichroism, resolution enhanced native acidic gel electrophoresis (RENAGE), electron microscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence and proteinase K resistance. Our results show that shaking causes the formation of β-sheet rich oligomers with a population distribution ranging from octamers to dodecamers and that further shaking causes a transition to β-sheet fibrils. In addition, we show that shaking-induced conversion occurs for a wide range of full-length and truncated constructs of mouse, hamster and cervid prion proteins. We propose that this method of conversion provides a robust, reproducible and easily accessible model for scrapie-like amyloid formation, allowing the generation of milligram quantities of physiologically stable β-sheet rich oligomers and fibrils. These results may also have interesting implications regarding our understanding of prion conversion and propagation both within the brain and via techniques such as protein misfolding cyclic amplification (PMCA) and quaking induced conversion (QuIC).

Dataset Information

αB-Crystallin Chaperone Inhibits Aβ Aggregation by Capping the β-Sheet-Rich Oligomers and Fibrils.

Publications

αB-Crystallin Chaperone Inhibits Aβ Aggregation by Capping the β-Sheet-Rich Oligomers and Fibrils.

Similar Datasets

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