Cooperative Transition between Open and Closed Conformations in Potassium Channels

Potassium (K+) ion channels switch between open and closed conformations. The nature of this important transition was revealed by comparing the X-ray crystal structures of the MthK channel from Methanobacterium thermoautotrophicum, obtained in its open conformation, and the KcsA channel from Streptomyces lividans, obtained in its closed conformation. We analyzed the dynamic characteristics and energetics of these homotetrameric structures in order to study the role of the intersubunit cooperativity in this transition. For this, elastic models and in silico alanine-scanning mutagenesis were used, respectively. Reassuringly, the calculations manifested motion from the open (closed) towards the closed (open) conformation. The calculations also revealed a network of dynamically and energetically coupled residues. Interestingly, the network suggests coupling between the selectivity filter and the gate, which are located at the two ends of the channel pore. Coupling between these two regions was not observed in calculations that were conducted with the monomer, which emphasizes the importance of the intersubunit interactions within the tetrameric structure for the cooperative gating behavior of the channel.Author Summary: Potassium channels are found, in essence, in all kingdoms of life and all types of cells, and they are involved in key biological processes. For example, they are involved in the generation and propagation of nerve impulses in the synapse and neuron. Mutations in the proteins that form the channel may lead to diseases, such as multiple sclerosis, cystic fibrosis, and cardiac arrhythmia. Because of their involvement in these and other channelopathies, i.e., channel-related diseases, they are major drug targets. The channels switch between open (ion-conducting) and closed conformations. The structural characteristics of the transition between these conformations were studied using X-ray crystallography, spectroscopic, and single-molecule techniques, as well as computations. Here we used normal-mode analysis and in silico alanine-scanning mutagenesis to understand the molecular underpinnings of this transition. Our results suggest that the transition is mediated through a network of amino acids that are coupled to each other and connect the two ends of the pore. The importance of many of these residues was noted in previous empirical studies. The calculations also suggest that interactions between subunits of the homotetrameric structure of the channel contribute to the transition. The approach may also be useful to elucidate the mechanism of other transmembrane proteins in molecular details and to suggest key amino acids that are functionally important.