Department of Anesthesiology

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Mechanism for selectivity-inactivation coupling in KcsA potassium channels.

TitleMechanism for selectivity-inactivation coupling in KcsA potassium channels.
Publication TypeJournal Article
Year of Publication2011
AuthorsCheng WWL, McCoy JG, Thompson AN, Nichols CG, Nimigean CM
JournalProc Natl Acad Sci U S A
Volume108
Issue13
Pagination5272-7
Date Published2011 Mar 29
ISSN1091-6490
KeywordsBacterial Proteins, Ion Channel Gating, Models, Molecular, Molecular Sequence Data, Potassium, Potassium Channels, Protein Conformation, Rubidium Radioisotopes, Sodium Radioisotopes, X-Ray Diffraction
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.

DOI10.1073/pnas.1014186108
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21402935
PubMed Central IDPMC3069191
Grant ListGM-0080 / GM / NIGMS NIH HHS / United States
GM088352 / GM / NIGMS NIH HHS / United States
R01 GM088352-02 / GM / NIGMS NIH HHS / United States
R01-GM077560 / GM / NIGMS NIH HHS / United States
R01-HL54171 / HL / NHLBI NIH HHS / United States