Interaction of arsenic with gap junction protein connexin 43 alters gap junctional intercellular communication
Interaction of arsenic with gap junction protein connexin 43 alters gap junctional intercellular communication
复制标题
DOI：
10.1016/j.bbamcr.2018.07.014
复制
发表时间：
2018-10-01
影响因子：
5.1
通讯作者：
Das Sarma, Jayasri
中科院分区：
文献类型：
--
作者：
Hussain, Afaq;Das Sarma, Subhajit;Das Sarma, Jayasri
长期接触地下水砷污染是世界上最大的环境健康灾难之一。三价砷的毒性主要是由于其与蛋白质中的巯基相互作用而产生的。砷与蛋白质的结合可以改变蛋白质的构象并改变其与其他蛋白质的相互作用，从而导致组织损伤。因此，为了了解毒性的起源并探索治疗方法，砷结合蛋白的研究受到了极大的重视。在这里，我们研究砷对连接蛋白 43 (Cx43) 的动态影响，连接蛋白 43 (Cx43) 是一种形成间隙连接的蛋白质，其改变严重扰乱了对维持组织稳态至关重要的细胞间通讯。比较砷处理和未处理条件的计算机分子模型和体外研究显示出不同的结果。由于膜结合形式未改变的 Cx43 的可用性降低，砷严重破坏了间隙连接通讯。计算机和电感耦合等离子体质谱研究表明，砷与 Cx43 的相互作用优选通过表面暴露的半胱氨酸发生，从而封端在三级结构中形成二硫键的硫醇基团。这导致 Cx43 寡聚化的破坏，并且改变的 Cx43 无法运输到膜表面，通常形成主要定位于内质网的聚集体。细胞表面功能性 Cx43 的缺失会对细胞稳态产生有害影响，导致细胞选择性死亡和组织损伤。
Chronic exposure to Arsenic pollution in ground water is one of the largest environmental health disasters in the world. The toxicity of trivalent Arsenicals primarily happens due to its interaction with sulfhydryl groups in proteins. Arsenic binding to the protein can change the conformation of the protein and alter its interactions with other proteins leading to tissue damage. Therefore, much importance has been given to the studies of Arsenic bound proteins, for the purpose of understanding the origins of toxicity and to explore therapeutics. Here we study the dynamic effect of Arsenic on Connexin 43 (Cx43), a protein that forms the gap junctions, whose alteration deeply perturbs the cell-to-cell communication vital for maintaining tissue homeostasis. In silico molecular modelling and in vitro studies comparing Arsenic treated and untreated conditions show distinct results. Gap junction communication is severely disrupted by Arsenic due to reduced availability of unaltered Cx43 in the membrane bound form. In silico and Inductively Coupled Plasma Mass Spectrometry studies revealed the interaction of Arsenic to the Cx43 preferably occurs through surface exposed cysteines, thereby capping the thiol groups that form disulfide bonds in the tertiary structure. This leads to disruption of Cx43 oligomerization, and altered Cx43 is incompetent for transportation to the membrane surface, often forming aggregates primarily localizing in the endoplasmic reticulum. Loss of functional Cx43 on the cell surface have a deleterious effect on cellular homeostasis leading to selective vulnerability to cell death and tissue damage.