User:Murtaza Anssar/Sandbox1 connexin

From Proteopedia

Heart disease is the leading cause of death for both men and women in the United States. Statistics show that over 80 million people in the United States have some form of cardiovascular disease which is responsible for 1 in every 2.8 deaths. At the molecular level the causes are primarily due to defective connexins. Connexins are subunits that make up a connexon, a gap junction channel that is involved in cell to cell communication in many organs, and are of crucial importance to the heart. In the heart, connexins are needed for myocardial synchronization and optimal heart function. Any kind of defect or blockage of these connexin channels would therefore lead to interrupted electrical flow and decreased cardiac performance. The most common conditions associated with defective connexin pathways in the heart are arrhythmias or abnormal heart rhythms. The main connexin involved in intercellular communication is connexin 43 which is abundantly present in the heart, however, the precise function is not clearly understood due to the absence of a known structure. We have generated a three dimensional physical model of a connexon made by connexin 26 subunits, in order to understand specific features of the channel that relates to its isoform. Specifically, we have selected residues that play a key role in permeability, intercellular docking and pore funnel formation. One connexin was selected (blue) to highlight all these features. Residues involved in the intercellular interactions of the two connexons that form the gap junction channels are Leu56, Lys168, Asp179, Asn176 and Thr177 (alpha carbons in orange and amino acids in CPK color scheme). Secondary structures in these regions are highlighted (green) and represent beta sheets. The residues involved in formation of the pore funnel are Thr5 and Met34 (yellow) which interact with Asp2 and Trp3 (purple) of an adjacent connexin. It has been observed that Trp3 forms a hydrophobic interaction with Met34 which is thought to keep the channel in an open state. Thr5 forms a hydrogen bond with Asp2. Another group of residues that contribute in regulating the permeability of this channel are Asp 50 and Asp46 (magenta), which are involved in creating a 9Å long, negatively charged path. This is believed to create selectivity for small, positively charged molecules. This model will help in future research in heart therapy. If we understand what affects permeability in connexin 43, we can solve many problems related to electrical and molecular coupling such as slow velocity which is involved in arrythmias.

Introduction