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Arsenite interferes with protein folding and triggers formation of protein aggregates in yeast.

Journal article
Authors Therese Jacobson
Clara Navarrete
Sandeep K Sharma
Theodora C Sideri
Sebastian Ibstedt
Smriti Priya
Chris M Grant
Philipp Christen
Pierre Goloubinoff
Markus J. Tamás
Published in Journal of cell science
Volume 125
Issue 21
Pages 5073-83
ISSN 1477-9137
Publication year 2012
Published at Department of Chemistry and Molecular Biology
Pages 5073-83
Language en
Links dx.doi.org/10.1242/jcs.107029
Subject categories Biochemistry, Cell and molecular biology, Molecular biology, Microbiology

Abstract

Several metals and metalloids profoundly affect biological systems, but their impact on the proteome and mechanisms of toxicity are not fully understood. Here, we demonstrate that arsenite causes protein aggregation in Saccharomyces cerevisiae. Various molecular chaperones were found to be associated with arsenite-induced aggregates indicating that this metalloid promotes protein misfolding. Using in vivo and in vitro assays, we show that proteins in the process of synthesis/folding are particularly sensitive to arsenite-induced aggregation, that arsenite interferes with protein folding by acting on unfolded polypeptides, and that arsenite directly inhibits chaperone activity. Thus, folding inhibition contributes to arsenite toxicity in two ways: by aggregate formation and by chaperone inhibition. Importantly, arsenite-induced protein aggregates can act as seeds committing other, labile proteins to misfold and aggregate. Our findings describe a novel mechanism of toxicity that may explain the suggested role of this metalloid in the etiology and pathogenesis of protein folding disorders associated with arsenic poisoning.

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