National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
United States
Citation
Journal: Sci Adv / Year: 2023 Title: Eukaryotic Kv channel Shaker inactivates through selectivity filter dilation rather than collapse. Authors: Robyn Stix / Xiao-Feng Tan / Chanhyung Bae / Ana I Fernández-Mariño / Kenton J Swartz / José D Faraldo-Gómez / Abstract: Eukaryotic voltage-gated K channels have been extensively studied, but the structural bases for some of their most salient functional features remain to be established. C-type inactivation, for ...Eukaryotic voltage-gated K channels have been extensively studied, but the structural bases for some of their most salient functional features remain to be established. C-type inactivation, for example, is an auto-inhibitory mechanism that confers temporal resolution to their signal-firing activity. In a recent breakthrough, studies of a mutant of Shaker that is prone to inactivate indicated that this process entails a dilation of the selectivity filter, the narrowest part of the ion conduction pathway. Here, we report an atomic-resolution cryo-electron microscopy structure that demonstrates that the wild-type channel can also adopt this dilated state. All-atom simulations corroborate this conformation is congruent with the electrophysiological characteristics of the C-type inactivated state, namely, residual K conductance and altered ion specificity, and help rationalize why inactivation is accelerated or impeded by certain mutations. In summary, this study establishes the molecular basis for an important self-regulatory mechanism in eukaryotic K channels, laying a solid foundation for further studies.
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