Evolutionary coupling in the K_V1.2-β₂ complex

K_V1.2 is a potassium channel protein whose electrophysiological properties, including an oxygen sensing response, are modulated by auxiliary beta subunits. The beta subunits are homologous to oxidoreductases, supporting a hypothesis that the coupling of the two subunits helps connect the redox state of the cell to the electrical activity of the membrane. however the exact mechanism of the coupling has not been discovered to-date. We apply evolutionary correlation analysis to infer previously unknown components of the interaction network regulating the response to hypoxia of the K_V1.2/ β₂ complex. Briefly, evolutionary correlation analysis involves finding correlated amino acid substitutions in functionally equivalent proteins (for both subunits) across a range of species. The method thus depends on a reliable method of inferring functionally equivalent (orthologous) proteins in different species, which method we describe in a paper recently published in pLoS ONe. One key finding is the characterization of a network of motif interactions between the α and the β subunits. By significance testing, we show that the likelihood of the correlations shown in the K _V1.2-β two interaction motifs arising by chance is less than 0.0003, which shows that the correlations are statistically highly significant. We therefore believe that the correlations are likely to be biologically relevant. Other major findings are correlations between specific motifs in the K_V1.2-β₂ complex and motifs in other proteins such as RACK1 and eif3s6ip, which in turn are connected to the hypoxia response. Our paper combines this correlation with the literature evidence on potassium channel inactivation and hypoxia response to identify specific motifs to serve as experimental targets for studies focused on this response. This work aims to add to our general understanding of two major issues in ion channel science: (1) how multi-protein complexes including ion channels function in coordinated fashion and (2) how ion channels mediate the conversation between the intracellular and extracellular environments. We also aim to apply to ion channel science the principle that domain-domain interactions in proteins can be inferred from correlation of amino-acid substitutions in sets of functionally equivalent proteins.