Mechanism for Selectivity-inactivation Coupling in KcsA Potassium Channels

Journal Article · Sat Dec 31 04:00:00 EST 2011 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1014186108· OSTI ID:1041664

Cheng, W; McCoy, J; Thompson, A; Nichols, C; Nimigean, C

Structures of the prokaryotic K{sup +} 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{sup +} 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{sup +} selectivity. In E71A channels, Na{sup +} permeates at higher rates as seen with {sup 86}Rb{sup +} and {sup 22}Na{sup +} flux measurements and analysis of intracellular Na{sup +} block. Crystal structures of E71A reveal that the selectivity filter no longer assumes the 'collapsed,' presumed inactivated, conformation in low K{sup +}, but a 'flipped' conformation, that is also observed in high K{sup +}, high Na{sup +}, and even Na{sup +} only conditions. The data reveal the importance of the E71-D80 interaction in both favoring inactivation and maintaining high K{sup +} selectivity. We propose a molecular mechanism by which inactivation and K{sup +} selectivity are linked, a mechanism that may also be at work in other channels containing the canonical GYG signature sequence.

• Research Organization: BROOKHAVEN NATIONAL LABORATORY (BNL)
• Sponsoring Organization: USDOE SC OFFICE OF SCIENCE (SC)
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 1041664
• Report Number(s): BNL--97342-2012-JA
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 13 Vol. 108; ISSN 0027-8424; ISSN PNASA6
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARBONYLS
CATIONS
CRYSTAL STRUCTURE
INACTIVATION
MUTANTS
POTASSIUM