Non-native Proteins as Newly-Identified Targets of Heavy Metals and Metalloids

Abstract

Heavy metal ions such as Cd²⁺, Hg²⁺ and Pb²⁺ as well as metalloid arsenic(III) species very efficiently inhibit the refolding of chemically denatured proteins (IC₅₀ values in nanomolar range). In their presence, the proteins misfold and aggregate. Denatured proteins appear to be much more susceptible to form high-affinity pluridentate complexes with heavy metals and metalloids than native proteins. In a denatured protein, the potential ligands of metal ions, the most important ones being cysteine and histidine residues, are more easily accessible for the toxic agents; moreover, denatured proteins with more flexible and motile backbones are more likely than folded native proteins to tolerate the formation of pluridentate protein–metal complexes with their defined geometry. In cells, the interference of metals with nascent and other non-native forms of proteins might manifest itself both in a quantitative deficiency of the affected proteins and the formation of proteotoxic aggregates. Possibly, the toxic effects of heavy metals and metalloids arise not only from their interaction with specific, particularly susceptible native proteins but also from a general derailing of protein folding . The toxic scope of heavy metals and metalloids thus could be more pleiotropic and extensive than assumed so far.