title: 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.
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ibstedt
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK Current address: Department of Genetics, Evolution and Environment and UCL Cancer Institute, University College London, WC1E 6BT, London, UK.
authors.forename: Theodora C
authors.initials: TC
authors.lastname: Sideri
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Grant
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, S-405 30 Gothenburg, Sweden markus.tamas@cmb.gu.se.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Tamás
keywords: arsenite; chaperone; protein aggregation; protein folding; translation