Voltage sensor conformations in the open and closed states in rosetta structural models of K + channels

Abstract

Voltage-gated ion channels control generation and propagation of action potentials in excitable cells. Significant progress has been made in understanding structure and function of the voltage-gated ion channels, highlighted by the high-resolution open-state structure of the voltage-gated potassium channel, K v 1.2. However, because the structure of the closed state is unknown, the gating mechanism remains controversial. We adapted the rosetta membrane method to model the structures of the K v 1.2 and KvAP channels using homology, de novo , and domain assembly methods and selected the most plausible models using a limited number of experimental constraints. Our model of K v 1.2 in the open state is very similar in overall topology to the x-ray structure of this channel. Modeling of KvAP in the open state suggests that orientation of the voltage-sensing domain relative to the pore-forming domain is considerably different from the orientation in the K v 1.2 open state and that the magnitude of the vertical movement of S4 is significantly greater. Structural modeling of closed state of K v 1.2 suggests gating movement that can be viewed as a sum of two previously suggested mechanisms: translation (2–4 Å) plus rotation (≈180°) of the S4 segment as proposed in the original “sliding helix” or “helical screw” models coupled with a rolling motion of the S1–S3 segments around S4, similar to recent “transporter” models of gating. We propose a unified mechanism of voltage-dependent gating for K v 1.2 and KvAP in which this major conformational change moves the gating charge across the electric field in an analogous way for both channels.