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

Li, Jing; Ostmeyer, Jared; Cuello, Luis G.; Perozo, Eduardo; Roux, Benoît

doi:10.1085/jgp.201812082

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

Journal Article · Thu Aug 02 00:00:00 EDT 2018 · Journal of General Physiology

DOI:https://doi.org/10.1085/jgp.201812082· OSTI ID:1462596

Li, Jing; Ostmeyer, Jared;

; Perozo, Eduardo;

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.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: 1S10OD018495-01

OSTI ID:: 1462596

Journal Information:: Journal of General Physiology, Journal Name: Journal of General Physiology Vol. 150 Journal Issue: 10; ISSN 0022-1295

Publisher:: Rockefeller University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 48 works

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