Mechanism for selectivity-inactivation coupling in KcsA potassium channels.

Abstract

Structures of the prokaryotic K(+) channel, KcsA, highlight the role of the selectivity filter carbonyls from the GYG signature sequence in determining a highly selective pore, but channels displaying this sequence vary widely in their cation selectivity. Furthermore, variable selectivity can be found within the same channel during a process called C-type inactivation. We investigated the mechanism for changes in selectivity associated with inactivation in a model K(+) channel, KcsA. We found that E71A, a noninactivating KcsA mutant in which a hydrogen-bond behind the selectivity filter is disrupted, also displays decreased K(+) selectivity. In E71A channels, Na(+) permeates at higher rates as seen with and flux measurements and analysis of intracellular Na(+) block. Crystal structures of E71A reveal that the selectivity filter no longer assumes the "collapsed," presumed inactivated, conformation in low K(+), but a "flipped" conformation, that is also observed in high K(+), high Na(+), and even Na(+) only conditions. The data reveal the importance of the E71-D80 interaction in both favoring inactivation and maintaining high K(+) selectivity. We propose a molecular mechanism by which inactivation and K(+) selectivity are linked, a mechanism that may also be at work in other channels containing the canonical GYG signature sequence.

DOI: 10.1073/pnas.1014186108

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@article{Cheng2011MechanismFS, title={Mechanism for selectivity-inactivation coupling in KcsA potassium channels.}, author={Wayland W.L. Cheng and Jason McCoy and Ameer N. Thompson and Colin G. Nichols and Crina M Nimigean}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2011}, volume={108 13}, pages={5272-7} }