title: 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.
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA.
authors.forename: Wayland W L
authors.initials: WW
authors.lastname: Cheng
authors.forename: Jason G
authors.initials: JG
authors.lastname: McCoy
authors.forename: Ameer N
authors.initials: AN
authors.lastname: Thompson
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.forename: Crina M
authors.initials: CM
authors.lastname: Nimigean
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012414:Rubidium Radioisotopes / Q000737:chemistry / Q000378:metabolism; D012979:Sodium Radioisotopes; D014961:X-Ray Diffraction
chemical_list: D001426:Bacterial Proteins; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D012979:Sodium Radioisotopes; C107790:prokaryotic potassium channel; D011188:Potassium