Interaction of arsenic with gap junction protein connexin 43 alters gap junctional intercellular communication

Hussain, Afaq and Das Sarma, Subhajit and Babu, Swathy and Pal, Debnath and Das Sarma, Jayasri (2018) Interaction of arsenic with gap junction protein connexin 43 alters gap junctional intercellular communication. In: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 1865 (10). pp. 1423-1436.

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Abstract

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.

Item Type:	Journal Article
Publication:	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Publisher:	ELSEVIER SCIENCE BV
Additional Information:	Copy right for this article belong to ELSEVIER SCIENCE BV
Keywords:	Arsenic toxicity; Gap junctions; Connexin 43; Gap junction intercellular communication (GJIC); Altered cellular homeostasis
Department/Centre:	Division of Interdisciplinary Sciences > Supercomputer Education & Research Centre
Date Deposited:	01 Oct 2018 15:01
Last Modified:	01 Oct 2018 15:01
URI:	http://eprints.iisc.ac.in/id/eprint/60786

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