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Biomolecules. 2014 Feb 25;4(1):252-67. doi: 10.3390/biom4010252.

Heavy metals and metalloids as a cause for protein misfolding and aggregation.

Author information

1
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg S-405 30, Sweden. markus.tamas@cmb.gu.se.
2
Department of Biochemistry, University of Zurich, Zürich CH-8057, Switzerland. s.sharma@bioc.uzh.ch.
3
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg S-405 30, Sweden. sebastian.ibstedt@cmb.gu.se.
4
Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg S-405 30, Sweden. therese.jacobson@cmb.gu.se.
5
Department of Biochemistry, University of Zurich, Zürich CH-8057, Switzerland. christen@bioc.uzh.ch.

Abstract

While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders.

PMID:
24970215
PMCID:
PMC4030994
DOI:
10.3390/biom4010252
[Indexed for MEDLINE]
Free PMC Article

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