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Title: Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel

Abstract

C-type inactivation is a time-dependent process observed in many K+ channels whereby prolonged activation by an external stimulus leads to a reduction in ionic conduction. While C-type inactivation is thought to be a result of a constriction of the selectivity filter, the local dynamics of the process remain elusive. Here, we use molecular dynamics (MD) simulations of the KcsA channel to elucidate the nature of kinetically delayed activation/inactivation gating coupling. Microsecond-scale MD simulations based on the truncated form of the KcsA channel (C-terminal domain deleted) provide a first glimpse of the onset of C-type inactivation. We observe over multiple trajectories that the selectivity filter consistently undergoes a spontaneous and rapid (within 1–2 µs) transition to a constricted conformation when the intracellular activation gate is fully open, but remains in the conductive conformation when the activation gate is closed or partially open. Multidimensional umbrella sampling potential of mean force calculations and nonequilibrium voltage-driven simulations further confirm these observations. Electrophysiological measurements show that the truncated form of the KcsA channel inactivates faster and greater than full-length KcsA, which is consistent with truncated KcsA opening to a greater degree because of the absence of the C-terminal domain restraint. Together, these results imply thatmore » the observed kinetics underlying activation/inactivation gating reflect a rapid conductive-to-constricted transition of the selectivity filter that is allosterically controlled by the slow opening of the intracellular gate.« less

Authors:
 [1];  [1]; ORCiD logo [2];  [1]; ORCiD logo [1]
  1. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL
  2. Department of Cell Physiology and Molecular Biophysics, Texas Tech University Health Sciences Center, Lubbock, TX
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1462596
Grant/Contract Number:  
1S10OD018495-01
Resource Type:
Published Article
Journal Name:
Journal of General Physiology
Additional Journal Information:
Journal Name: Journal of General Physiology Journal Volume: 150 Journal Issue: 10; Journal ID: ISSN 0022-1295
Publisher:
Rockefeller University Press
Country of Publication:
United States
Language:
English

Citation Formats

Li, Jing, Ostmeyer, Jared, Cuello, Luis G., Perozo, Eduardo, and Roux, Benoît. Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. United States: N. p., 2018. Web. doi:10.1085/jgp.201812082.
Li, Jing, Ostmeyer, Jared, Cuello, Luis G., Perozo, Eduardo, & Roux, Benoît. Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. United States. doi:10.1085/jgp.201812082.
Li, Jing, Ostmeyer, Jared, Cuello, Luis G., Perozo, Eduardo, and Roux, Benoît. Thu . "Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel". United States. doi:10.1085/jgp.201812082.
@article{osti_1462596,
title = {Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel},
author = {Li, Jing and Ostmeyer, Jared and Cuello, Luis G. and Perozo, Eduardo and Roux, Benoît},
abstractNote = {C-type inactivation is a time-dependent process observed in many K+ channels whereby prolonged activation by an external stimulus leads to a reduction in ionic conduction. While C-type inactivation is thought to be a result of a constriction of the selectivity filter, the local dynamics of the process remain elusive. Here, we use molecular dynamics (MD) simulations of the KcsA channel to elucidate the nature of kinetically delayed activation/inactivation gating coupling. Microsecond-scale MD simulations based on the truncated form of the KcsA channel (C-terminal domain deleted) provide a first glimpse of the onset of C-type inactivation. We observe over multiple trajectories that the selectivity filter consistently undergoes a spontaneous and rapid (within 1–2 µs) transition to a constricted conformation when the intracellular activation gate is fully open, but remains in the conductive conformation when the activation gate is closed or partially open. Multidimensional umbrella sampling potential of mean force calculations and nonequilibrium voltage-driven simulations further confirm these observations. Electrophysiological measurements show that the truncated form of the KcsA channel inactivates faster and greater than full-length KcsA, which is consistent with truncated KcsA opening to a greater degree because of the absence of the C-terminal domain restraint. Together, these results imply that the observed kinetics underlying activation/inactivation gating reflect a rapid conductive-to-constricted transition of the selectivity filter that is allosterically controlled by the slow opening of the intracellular gate.},
doi = {10.1085/jgp.201812082},
journal = {Journal of General Physiology},
number = 10,
volume = 150,
place = {United States},
year = {2018},
month = {8}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1085/jgp.201812082

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Cited by: 5 works
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