Misfolding and aggregation of nascent proteins: a novel mode of toxic cadmium action in vivo

Abstract

Cadmium is a highly poisonous metal and a human carcinogen, but the molecular mechanisms underlying its cellular toxicity are not fully understood. Recent findings in yeast cells indicate that cadmium exerts its deleterious effects by inducing widespread misfolding and aggregation of nascent proteins. Here, we discuss this novel mode of toxic heavy metal action and propose a mechanism by which molecular chaperones may reduce the damaging effects of heavy metal ions on protein structures.

Keywords: Cadmium; Metal toxicity; Molecular chaperones; Protein aggregation; Protein folding; Saccharomyces cerevisiae.

Fig. 1

Mechanisms by which unfolding chaperones may reduce protein damage by heavy metal ions. A de novo synthetized or stress-unfolded polypeptide (top), can fold spontaneously into native, biologically active, harmless protein (left, smiley), or interact with a heavy metal ion (triangle) and misfold into a non-functional toxic species (middle, skull) that may further catalyse the misfolding of unfolded polypeptides, even when heavy metal ions are sub-stoichiometric, into more non-functional toxic species (right, skull). By their unfolding action, molecular chaperones (red arrows) may reduce the concentration of seeds that catalyse the formation of toxic protein aggregates