The Principle Of Cooperative Gating In A Calcium-gated Potassium Channel

The cooperative gating of ion channels permits a sensitive response to a small change of the external stimulus in the cellular context, and thus regulates the channel activity. Although ion channel cooperativity was recognized more than30years ago, the mechanism remains elusive.The steep dependence of channel opening on an appropriate stimulus allows ion channels to turn on almost like a switch. Here we show how binding of the first Ca2+ion in one of the eight chemically identical subunits facilitates the other Ca2+-binding events in MthK, a Ca2+-gated K+channel, by analyzing a large collection of MthK gating ring structures, and the corresponding thermodynamic and electrophysiological measurements. These structural and functional studies lead us to conclude that the Ca2+-binding sites of the MthK channel alternate between two quaternary states and exhibit significant differences in Ca2+affinity. The binding of Ca2+at one site within the octameric gating ring of MthK increases the Ca2+-affinity at the remaining unoccupied sites, and thus allow Ca2+to bind more easily. We demonstrate that conformational changes and dynamic motions of different parts of the gating ring collaborate with each other, and propose a cooperative model of MthK gating ring action illustrating a cascade of structural events that connect the initial Ca2+-binding to the final changes in Ca2+-binding affinities at the remaining unoccupied sites. The gating ring changes its quaternary state correspondingly for the transduction of the free energy of Ca2+-binding into mechanical work to open the ion conduction pore.We report the first cooperative structural model of the MthK channel at the atomic level, and our work opens a window to elucidate the cooperativity mechanism that underlies the gating process of ion channels.