Mercury-induced aggregation of human lens γ-crystallins reveals a potential role in cataract disease
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Cataract disease results from non-amyloid aggregation of eye lens proteins and is the leading cause of blindness in the world. A variety of studies have implicated both essential and xenobiotic metals as potential etiological agents in cataract disease. Essential metal ions, such as copper and zinc, are known to induce the aggregation in vitro of human γD crystallin, one of the more abundant γ-crystallins in the core of the lens. In this study, we expand the investigation of metal–crystallin interactions to heavy metal ions, such as divalent lead, cadmium and mercury. The impact of these metal ions in the non-amyloid aggregation, protein folding and thermal stability of three homologous human lens γ-crystallins has been evaluated using turbidity assays, electron microscopy, electronic absorption and circular dichroism spectroscopies. Our results show that Hg(II) ions can induce the non-amyloid aggregation of human γC and γS crystallins, but not γD crystallin. The mechanism of Hg-induced aggregation involves direct metal–protein interactions, loss of thermal stability, partial unfolding of the N-terminal domain of these proteins, and formation of disulfide-bridged dimers. Putative Hg(II) binding sites in γ-crystallins involved in metal-induced aggregation are discussed. This study reveals that mercury ions can induce the aggregation of human lens proteins, uncovering a potential role of this heavy metal ion in the bioinorganic chemistry of cataract disease.
KeywordsLens crystallins Human gamma crystallin Mercury Heavy metal ions Cataract disease
This research has been supported by the National Council for Science and Technology in Mexico (CONACYT Grant # 221134 to L.Q. and fellowships to J.A.D.C.), MIT-Seed Funds, NIH EY015834 Grant to J.A.K., and Fulbright-García Robles fellowship and Cátedra Marcos Moshinsky to L.Q. The authors would like to thank the technical assistance of Cammeron Haase-Pettingell (at MIT) and Lourdes Rojas at the Unit of Microscopy (Cinvestav).
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