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Global analysis of protein aggregation in yeast during physiological conditions and arsenite stress.

ABSTRACT: Protein aggregation is a widespread phenomenon in cells and associated with pathological conditions. Yet, little is known about the rules that govern protein aggregation in living cells. In this study, we biochemically isolated aggregation-prone proteins and used computational analyses to identify characteristics that are linked to physiological and arsenite-induced aggregation in living yeast cells. High protein abundance, extensive physical interactions, and certain structural properties are positively correlated with an increased aggregation propensity. The aggregated proteins have high translation rates and are substrates of ribosome-associated Hsp70 chaperones, indicating that they are susceptible for aggregation primarily during translation/folding. The aggregation-prone proteins are enriched for multiple chaperone interactions, thus high protein abundance is probably counterbalanced by molecular chaperones to allow soluble expression in vivo. Our data support the notion that arsenite interferes with chaperone activity and indicate that arsenite-aggregated proteins might engage in extensive aberrant protein-protein interactions. Expression of aggregation-prone proteins is down-regulated during arsenite stress, possibly to prevent their toxic accumulation. Several aggregation-prone yeast proteins have human homologues that are implicated in misfolding diseases, suggesting that similar mechanisms may apply in disease- and non-disease settings.

SUBMITTER: Ibstedt S

PROVIDER: S-EPMC4197440 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Global analysis of protein aggregation in yeast during physiological conditions and arsenite stress.

Ibstedt Sebastian S Sideri Theodora C TC Grant Chris M CM Tamás Markus J MJ

Biology open 20140912 10

Protein aggregation is a widespread phenomenon in cells and associated with pathological conditions. Yet, little is known about the rules that govern protein aggregation in living cells. In this study, we biochemically isolated aggregation-prone proteins and used computational analyses to identify characteristics that are linked to physiological and arsenite-induced aggregation in living yeast cells. High protein abundance, extensive physical interactions, and certain structural properties are p ...[more]

PMID: 25217615

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Project description:Cataract, a major cause of visual impairment worldwide, is the opacification of the eye's crystalline lens due to aggregation of the crystallin proteins. The research reported here is aimed at investigating the aggregating behavior of ?-crystallin proteins in various incubation conditions. Thioflavin T binding assay, circular dichroism spectroscopy, 1-anilinonaphthalene-8-sulfonic acid fluorescence spectroscopy, intrinsic (tryptophan) fluorescence spectroscopy, light scattering, and electron microscopy were used for structural characterization. Molecular dynamics simulations and bioinformatics prediction were performed to gain insights into the ?D-crystallin mechanisms of fibrillogenesis. We first demonstrated that, except at pH 7.0 and 37°C, the aggregation of ?D-crystallin was observed to be augmented upon incubation, as revealed by turbidity measurements. Next, the types of aggregates (fibrillar or non-fibrillar aggregates) formed under different incubation conditions were identified. We found that, while a variety of non-fibrillar, granular species were detected in the sample incubated under pH 7.0, the fibrillogenesis of human ?D-crystallin could be induced by acidic pH (pH 2.0). In addition, circular dichroism spectroscopy, 1-anilinonaphthalene-8-sulfonic acid fluorescence spectroscopy, and intrinsic fluorescence spectroscopy were used to characterize the structural and conformational features in different incubation conditions. Our results suggested that incubation under acidic condition led to a considerable change in the secondary structure and an enhancement in solvent-exposure of the hydrophobic regions of human ?D-crystallin. Finally, molecular dynamics simulations and bioinformatics prediction were performed to better explain the differences between the structures and/or conformations of the human ?D-crystallin samples and to reveal potential key protein region involved in the varied aggregation behavior. Bioinformatics analyses revealed that the initiation of amyloid formation of human ?D-crystallin may be associated with a region within the C-terminal domain. We believe the results from this research may contribute to a better understanding of the possible mechanisms underlying the pathogenesis of senile nuclear cataract.

Dataset Information

Global analysis of protein aggregation in yeast during physiological conditions and arsenite stress.

Publications

Global analysis of protein aggregation in yeast during physiological conditions and arsenite stress.

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