Departamento de Química, Centro de Investigación y de Estudios Avanzados (Cinvestav), Mexico City, Mexico.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
J Biol Inorg Chem. 2018 Oct;23(7):1105-1118. doi: 10.1007/s00775-018-1607-z. Epub 2018 Aug 30.
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.
白内障疾病是由于眼晶状体蛋白的非淀粉样聚集引起的，是世界上导致失明的主要原因。许多研究表明，必需金属和外源性金属都是白内障疾病的潜在病因。已知必需金属离子，如铜和锌，能够诱导人γD 晶体蛋白在体外聚集，γD 晶体蛋白是人眼晶状体中含量最丰富的γ-晶体蛋白之一。在这项研究中，我们将金属-晶体蛋白相互作用的研究扩展到重金属离子，如二价铅、镉和汞。使用浊度测定法、电子显微镜、电子吸收和圆二色性光谱法评估了这些金属离子对三种同源人眼晶状体γ-晶体蛋白的非淀粉样聚集、蛋白质折叠和热稳定性的影响。我们的结果表明，Hg(II)离子可以诱导人γC 和 γS 晶体蛋白发生非淀粉样聚集，但不能诱导γD 晶体蛋白。Hg 诱导聚集的机制涉及直接的金属-蛋白相互作用、热稳定性丧失、这些蛋白的 N 端结构域部分展开以及形成二硫键桥联二聚体。讨论了参与金属诱导聚集的γ-晶体蛋白中的潜在 Hg(II)结合位点。这项研究揭示了汞离子可以诱导人眼晶状体蛋白聚集，揭示了这种重金属离子在白内障疾病生物无机化学中的潜在作用。
