Gating of the TrkH ion channel by its associated RCK protein TrkA (original) (raw)

TrkH belongs to a superfamily of K + transport proteins required for growth of bacteria in low external K + concentrations. The crystal structure of TrkH from Vibrio parahaemolyticus showed that TrkH resembles a K + channel, and may have a gating mechanism substantially different from K + channels. TrkH assembles with TrkA, a cytosolic protein comprising two Regulate-the-Conductance-of-K + , or RCK domains, which are found in certain K + channels and control their gating. However, fundamental questions on whether TrkH is an ion channel and how it is regulated by TrkA remain unresolved. Here we show single-channel activity of TrkH that is upregulated by ATP via TrkA. We report two structures of the tetrameric TrkA ring, one in complex with TrkH and one in isolation, in which the ring assumes two dramatically different conformations. These results suggest a mechanism for how ATP increases TrkH activity by inducing conformational changes in TrkA. K + is concentrated in all living cells and is essential for many physiological processes. In bacteria, homeostasis of K + is largely mediated by specialized K + transport proteins known as the Superfamily of K + Transporters, or SKT proteins 1 . The bacterial TrkH/TrkG/KtrB proteins form the largest sub-family of SKT proteins, and the crystal structure of TrkH from Vibrio parahaemolyticus, VpTrkH, was reported recently 2 . Each of the four connected homologous domains of TrkH resembles a subunit of the KcsA K + channel, comprising two transmembrane helices connected by a re-entrant P-loop (M1-P-M2) 3 , and the four domains encircle a central ion permeation pathway. In addition, TrkH has two structural features atypical of K + channels: a dimeric quaternary structure, with each protomer containing its own pore; and a long membrane-embedded loop, inserted into the middle of a pore-lining

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