Institute of Physical and Theoretical Chemistry, Eberhard-Karls-University of Tübingen, Tübingen, Germany.
PLoS One. 2011;6(8):e23048. doi: 10.1371/journal.pone.0023048. Epub 2011 Aug 2.
Cadmium is a toxic heavy metal ubiquitously present in the environment and subsequently in the human diet. Cadmium has been proposed to disrupt the endocrine system, targeting in particular the estrogen signaling pathway already at environmentally relevant concentrations. Thus far, the reports on the binding affinity of cadmium towards human estrogen receptor alpha (hERα) have been contradicting, as have been the reports on the in vivo estrogenicity of cadmium. Hence, the mode of interaction between cadmium and the receptor remains unclear. Here, we investigated the interaction between cadmium and hERα on a molecular level by applying a novel, label-free biosensor technique based on reflectometric interference spectroscopy (RIfS). We studied the binding of cadmium to hERα, and the conformation of the receptor following cadmium treatment. Our data reveals that cadmium interacts with the ligand binding domain (LBD) of the ERα and affects the conformation of the receptor. However, the binding event, as well as the induced conformation change, greatly depends on the accessibility of the cysteine tails in the LBD. As the LBD cysteine residues have been reported as targets of post-translational modifications in vivo, we present a hypothesis according to which different cellular pools of ERα respond to cadmium differently. Our proposed theory could help to explain some of the previously contradicting results regarding estrogen-like activity of cadmium.
镉是一种普遍存在于环境中的有毒重金属，随后也会进入人类的饮食中。镉已被提出可破坏内分泌系统，特别是在环境相关浓度下靶向雌激素信号通路。到目前为止，关于镉与人雌激素受体α（hERα）结合亲和力的报告一直存在矛盾，关于镉体内雌激素活性的报告也是如此。因此，镉与受体之间的相互作用方式仍不清楚。在这里，我们通过应用一种基于反射干涉光谱学（RIfS）的新型无标记生物传感器技术，在分子水平上研究了镉与 hERα 之间的相互作用。我们研究了镉与 hERα 的结合，以及镉处理后受体的构象。我们的数据表明，镉与 ERα 的配体结合域（LBD）相互作用，并影响受体的构象。然而，结合事件以及诱导的构象变化在很大程度上取决于 LBD 中半胱氨酸尾巴的可及性。由于 LBD 中的半胱氨酸残基已被报道为体内翻译后修饰的靶标，我们提出了一个假设，即 ERα 的不同细胞池对镉的反应不同。我们提出的理论可以帮助解释一些先前关于镉类雌激素活性的相互矛盾的结果。
