Conformational Changes that Opens TrkH Ion Channel

Abstract

All living cells must accumulate a high intracellular concentration of K+ to maintain essential physiological functions. While in animals, K+ uptake is mediated by the well-studied Na+/K+ transporters, bacteria, yeast and plants accumulate K+ with a superfamily of K+ transporters known as the SKT proteins. TrkH is a member of the SKT family that assembles with a cytosolic domain, TrkA. Previously, we have shown that TrkH is an ion channel regulated by binding of ATP or ADP to the TrkA protein: ATP activates the channel while ADP inhibits it (1). We have also solved the crystal structures of TrkH and TrkH in complex with TrkA (1, 2). The structure of TrkH shows that it forms a homodimer and that each protomer has an ion conduction pore with an architecture similar to that of a K+ channel. The structure also revealed a feature not observed in K+ channels: a loop within the transmembrane region that blocks the ion permeation pathway. Further structural and functional analyses showed that the position of this loop is likely controlled by conformational changes on TrkA, which is in turn controlled by binding of ATP or ADP. We have applied single-particle cryo-electron microscopy to visualize conformational changes associated with channel gating. Preliminary data show that the TrkH-TrkA complex likely assumes a different conformation than that observed in the crystal structure.1. Cao, Y. et al. 2013. Gating of the TrkH ion channel by its associated RCK protein TrkA. Nature 496:317-322.2. Cao, Y. et al. 2011. Crystal structure of a potassium ion transporter, TrkH. Nature 471:336-340.