Excitability is mediated by the T1 domain of the voltage-gated potassium channel

The T1 domain of voltage-gated K+ (Kv) channel is the N-terminal cytoplasmic part of the channel preceding the transmembrane pore domain of the channel. Several crystal structures of the T1 domain show that the four T1 subunits are arranged in a rotationally symmetric tetramer. The subunit interface of the T1 domain encodes the assembly specificity of intact functional Kv channels. Along the fourfold symmetry axis of the T1 tetramer, a water-filled cavity exists. K+ ions, however, do not pass through this T1 cavity. Instead, they are believed to enter the transmembrane pore through four identical inter-subunit spaces created between the membrane-facing C-terminal side of the T1 tetramer and the inner leaflet of the membrane. Several point mutations have been introduced into the putative membrane-facing region of the T1 tetramer. These mutations led to a systematic change of the channel's voltage sensitivity. Such functional change was accompanied by a distinct structural change in the C-terminal membrane-facing side of the T1 tetramer. Interestingly, a similar structural alteration that renders the channel more excitable is also induced by the binding of a cytoplasmic protein Kv beta subunit. Within this conformationally flexible part of the T1 tetramer, non-Shaker type Kv channel subunits invariably contain one Zn2+ per subunit. With the Kv4.2 T1, we demonstrated that the tetramer can be reversibly converted to monomers by chelating zinc away from the protein. The rate of removal of Zn2+ is pH-dependent. The structural ability of the T1 tetramer to alter conformation could be an essential property to mediate and process protein protein interaction events in the cytoplasm to control excitability of intact full-length Kv channels.