Mapping the sequence of conformational changes underlying selectivity filter gating in the Kv11.1 potassium channel

Wang, David T.; Hill, Adam P.; Mann, Stefan A.; Tan, Peter S.; Vandenberg, Jamie I.

doi:10.1038/nsmb.1966

Cited by 50 publications

(87 citation statements)

References 53 publications

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“…Here, we show that mutating the equivalent residue G377 to valine and phenylalanine in the turret of the Kv1.3 channel markedly attenuates Kv1.3 C-type inactivation. It is worth noting that mutational studies on the HERG (human ether-a-go-go related gene) channel also demonstrated a functional importance of the turret region for C-type inactivation (16).…”

Section: Discussionmentioning

confidence: 99%

“…It comprises a tetrameric assembly of two transmembrane helices (helices S5 and S6 in Kv channels) connected by a pore loop region consisting of a turret, the pore helix, and the selectivity filter. Although it is now evident that structural changes at the interface between K + channel protein and lipid play an important role during the gating process (8,(12)(13)(14)(15)(16), including the coupling of voltage-sensor movements to Kv channel activation (17)(18)(19)(20), detailed characterization of these structural changes and their implications for K + channel gating remain unresolved.…”

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confidence: 99%

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Importance of lipid–pore loop interface for potassium channel structure and function

Cruijsen

Nand

Weingarth

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Potassium (i.e., K + ) channels allow for the controlled and selective passage of potassium ions across the plasma membrane via a conserved pore domain. In voltage-gated K + channels, gating is the result of the coordinated action of two coupled gates: an activation gate at the intracellular entrance of the pore and an inactivation gate at the selectivity filter. By using solid-state NMR structural studies, in combination with electrophysiological experiments and molecular dynamics simulations, we show that the turret region connecting the outer transmembrane helix (transmembrane helix 1) and the pore helix behind the selectivity filter contributes to K + channel inactivation and exhibits a remarkable structural plasticity that correlates to K + channel inactivation. The transmembrane helix 1 unwinds when the K + channel enters the inactivated state and rewinds during the transition to the closed state. In addition to wellcharacterized changes at the K + ion coordination sites, this process is accompanied by conformational changes within the turret region and the pore helix. Further spectroscopic and computational results show that the same channel domain is critically involved in establishing functional contacts between pore domain and the cellular membrane. Taken together, our results suggest that the interaction between the K + channel turret region and the lipid bilayer exerts an important influence on the selective passage of potassium ions via the K + channel pore. membrane protein | ion channel | solid-state NMR spectroscopy P otassium (i.e., K + ) channels are embedded in the plasma membrane to control the selective passage of potassium ions across the lipid bilayer. The channels open and close their conduction pathway by sensing changes in physicochemical parameters such as pH, ligand concentration, and membrane voltage (1). Structure-function studies on voltage-gated K + (Kv) channels suggested that lipid molecules are an integral part of the voltage-sensing domains, which transfer during the gating process electrical charges across the cell membrane (2-4). In some of the available Kv channel crystal structures, lipid molecules appear most densely packed against the pore domain, presumably providing an appropriate environment for the stability and the operation of the gating machinery to open and close the conduction pathway. In general, the activity of Kv pore domains is thought to be determined by the activity of two gates in series, one for activation and one for inactivation. These gates jointly control the conduction of ions through the pore (5-11). The activation gate is located at the intracellular entrance of the pore and the inactivation gate is situated toward the extracellular entrance at the selectivity filter (i.e., C-type inactivation). In addition, some potassium channels possess close to the activation gate a receptor for an N-terminal inactivating domain (i.e., N-type inactivation).The K + channel pore domain is conserved across all K + channels. It comprises a tetrameric assembly of t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Importance of lipid–pore loop interface for potassium channel structure and function

Cruijsen

Nand

Weingarth

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In this study perturbations to the equilibrium of activation or inactivation gating parameters are reported as changes in the Gibbs free energy (⌬⌬G) of the transition, compared with WT, whereas perturbations to the rates of activation, deactivation, onset of inactivation, or recovery from inactivation are reported as changes in lnk relative to WT (Ϫ⌬lnk). Perturbations were considered relevant if they met two criteria as follows: first, that the ⌬G or lnk value was significantly different to WT (using ANOVA, p Ͻ 0.05), and second, if the Ϫ⌬lnk value was Ͼ Ϯ0.693 s Ϫ1 , which is equivalent to a doubling of the rate, or the ⌬⌬G value was Ͼ Ϯ0.5 kcal⅐mol Ϫ1 , which has previously been shown to be a biologically relevant cutoff for shifts in equilibria (57,58).…”

Section: Functional Role(s) Of the S1 Helix In Kv111 Channelsmentioning

confidence: 99%

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Phan

David

et al. 2017

Journal of Biological Chemistry

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Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels, but the role of this region of the channel is largely unexplored. In part, this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here, we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro-405 to Phe-431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His-402 and Tyr-403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in finetuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus, S1 region mutations would reduce both the action potential repolarizing current passed by Kv11

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“…Gating at the selectivity filter is commonly referred to as C-type inactivation. Although a conformational rearrangement of the selectivity filter (10) underlies the final step of inactivation gating, there is increasing evidence, from a variety of potassium channels (11)(12)(13), that more widespread rearrangements of the channel protein precede this final nonconducting conformation.…”

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confidence: 99%

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

Perry

Vandenberg

2013

Journal of Biological Chemistry

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Mapping the sequence of conformational changes underlying selectivity filter gating in the Kv11.1 potassium channel

Cited by 50 publications

References 53 publications

Importance of lipid–pore loop interface for potassium channel structure and function

Importance of lipid–pore loop interface for potassium channel structure and function

The S1 helix critically regulates the finely tuned gating of Kv11.1 channels

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

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