RT Journal Article
SR Electronic
T1 Molecular dissection of multiphase inactivation of the bacterial sodium channel Na<sub>V</sub>Ab
JF The Journal of General Physiology
JO J Gen Physiol
FD Rockefeller University Press
SP jgp.201711884
DO 10.1085/jgp.201711884
A1 Gamal El-Din, Tamer M.
A1 Lenaeus, Michael J.
A1 Ramanadane, Karthik
A1 Zheng, Ning
A1 Catterall, William A.
YR 2018
UL http://jgp.rupress.org/content/early/2018/11/30/jgp.201711884.abstract
AB Homotetrameric bacterial voltage-gated sodium channels share major biophysical features with their more complex eukaryotic counterparts, including a slow-inactivation mechanism that reduces ion-conductance activity during prolonged depolarization through conformational changes in the pore. The bacterial sodium channel NaVAb activates at very negative membrane potentials and inactivates through a multiphase slow-inactivation mechanism. Early voltage-dependent inactivation during one depolarization is followed by late use-dependent inactivation during repetitive depolarization. Mutations that change the molecular volume of Thr206 in the pore-lining S6 segment can enhance or strongly block early voltage-dependent inactivation, suggesting that this residue serves as a molecular hub controlling the coupling of activation to inactivation. In contrast, truncation of the C-terminal tail enhances the early phase of inactivation yet completely blocks late use-dependent inactivation. Determination of the structure of a C-terminal tail truncation mutant and molecular modeling of conformational changes at Thr206 and the S6 activation gate led to a two-step model of these gating processes. First, bending of the S6 segment, local protein interactions dependent on the size of Thr206, and exchange of hydrogen-bonding partners at the level of Thr206 trigger pore opening followed by the early phase of voltage-dependent inactivation. Thereafter, conformational changes in the C-terminal tail lead to late use-dependent inactivation. These results have important implications for the sequence of conformational changes that lead to multiphase inactivation of NaVAb and other sodium channels.