Molecular Determinants of Gating at the Potassium Channel Selectivity Filter

KcsA is a prokaryotic proton-gated potassium channel from Streptomyces lividans, whose open probability is modulated by transmembrane voltage but not by pH. Its gating is dominated at steady state by a previously unrecognized inactivation process that is mechanistically equivalent to the C-type inactivation associated with eukaryotic voltage-dependent K+ channels. This inactivation is a wide spread regulation process in ion channels, however the molecular mechanism and conformational changes during this process are not well understood. In KcsA, the inactivation process is suppressed by the E71A mutation at the C-terminal region of the pore helix. In addition, two KcsA (E71A) crystal structures reveal large structural excursions of the selectivity filter during ion conduction and provide a glimpse of the range of conformations available to this region of the channel during gating. The hydrogen-bond network at the selectivity filter (Glu71- Asp80 and Trp67-Asp80) is the driving force that promotes filter instability through a compression of the selectivity filter parallel to the permeation pathway, which energetically biases it towards the inactivated conformation. This mechanism found in KcsA might serve as the basis for C-type inactivation in the K+ channel family. Taken together, the results from this work provide a plausible framework to understand the molecular mechanism for C-type inactivation in K+ channels.