TABLE 1.

List of residues in cASIC with highest number of coevolution contacts

From the MISTIC analysis, the top 5% coevolving residues include highly conserved cysteine residues involved in disulfide bridges stabilizing the fold of subunits in the ENaC/Degenerin family. Trp-288 or Tyr-369 in γENaC, which is crucial for communicating allosteric signaling between the extracellular region and the transmembrane domains (20, 37), has a large number of 22 coevolution contacts. Highly conserved Gly-30 in the HG motif implicated in the PHA-1 disease also has a high coevolution contact number, 25, suggesting the structural importance of these allosteric sites in mediating the channel function in the ion channel family. A coevolution contact is considered significant by the MISTIC according to a z-score of >6.5 (36). Highly conserved cysteines are shown in boldface; the allosteric residue W288 is shown in blue; the disease-linked residue G30 is shown in red.