Structural basis for C-type inactivation in a Shaker family voltage-gated K
            <sup>+</sup>
            channel

Reddi, Ravikumar; Matulef, Kimberly; Riederer, Erika A; Whorton, Matthew R.; Valiyaveetil, Francis I.

doi:10.1126/sciadv.abm8804

Cited by 43 publications

(41 citation statements)

References 60 publications

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“…Our previous work on the Kv1.2 channel had predicted aspartate flipping, SF dilation and loss of K + ions from S0-S2, also using the CHARMM force field [31], before recent cryoEM structures of stably-inactivated Shaker W434F, Kv1.2 W362F and Kv1.3 channels became available ( Fig. 6 C-F ) [27,29,30]. In MthK, previous MD simulations done with the CHARMM force field (and reduced interaction strength between K + ions and carbonyl oxygens) revealed that K + ions from sites S1, S2, and S3 need to unbind before the SF collapse, which was then structurally similar to the one seen in KcsA, having a constriction at the level of the ‘first’ glycine (G61), V60 and G61 carbonyl flipping and increased number of water molecules behind the SF [32].…”

Section: Resultsmentioning

confidence: 99%

“…Structures of KcsA, stably-inactivated mutants of voltage-gated K + channels ( Shaker W434F and Kv1.2 W362F) and WT Kv1.3 channels revealed that C-type inactivation-related conformational changes at the SF can follow at least two distinct paths ( Fig. 6 ) [27][28][29][30] : in KcsA the SF pinches (constricts) at the level of the 'first' glycine (G77, corresponding to G61 in MthK), which is accompanied by flipping of valine (V76 in KcsA, corresponding to V60 in MthK) carbonyl away from the SF axis. The SF also loses two K + ions during inactivation, and has remaining ions bound at S1 and S4, whereas S3 is occupied by a water molecule, which presumably enhances the valine flipping.…”

Section: Longer In Silico Electrophysiology Simulationsmentioning

confidence: 99%

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Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Kopeć

Thomson

Groot

et al. 2022

Preprint

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K+ channel activity can be limited by C-type inactivation, which is likely initiated in part by dissociation of K+ ions from the selectivity filter, and modulated by side chains surrounding the selectivity filter. Whereas crystallographic and computational studies have linked inactivation to a 'collapsed' selectivity filter conformation in the KcsA channel, the structural basis for selectivity filter gating in other K+ channels has been less clear. Here, we combined electrophysiological recordings with molecular dynamics based, in silico electrophysiology simulations to study selectivity filter gating in the model potassium channel MthK and the MthK mutant V55E (analogous to KcsA E71) in the pore-helix. We find that MthK V55E has lower open probability than the WT channel, due to decreased stability of the open state. Simulations account for aspects of these observations on the atomistic scale, showing that ion permeation in V55E is differentially altered in two distinct orientations of the E55 side chain. In the 'vertical' orientation of E55, in which E55 forms a hydrogen bond with D64 (as observed with KcsA WT channels), the filter displays reduced conductance compared to MthK WT. In contrast, with 'horizontal' orientation, K+ conductance is similar to MthK WT; however the filter is less stable in the conductive conformation. Surprisingly, transitions of MthK WT and V55E channels to the non-conducting (inactivated) state observed in simulations are associated with a widening selectivity filter, unlike the narrowing selectivity filter observed with KcsA, and similar to recent structures of stably-inactivated Shaker W434F and Kv1.2 W362F mutants.

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Section: Resultsmentioning

confidence: 99%

Section: Longer In Silico Electrophysiology Simulationsmentioning

confidence: 99%

Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Kopeć

Thomson

Groot

et al. 2022

Preprint

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“…Sodium conduction across the C-type inactivated state has been experimentally observed in hERG and also in the voltage-gated Shaker channel . Furthermore, in recent experimental structures of a fast inactivating mutant of Shaker, both by cryo-EM and by X-ray crystallography, the SF appeared with binding sites S3 and S4 perfectly intact but with S1 and S2 sites enlarged compared to the canonical structure (Figure b). Thus, inactivation of Shaker seems to imply a widening of the extracellular portion of the SF rather than a constriction of its central region, as observed in the KcsA channel.…”

Section: Discussionmentioning

confidence: 99%

Early Steps in C-Type Inactivation of the hERG Potassium Channel

Pettini

Domene

Furini

2022

J. Chem. Inf. Model.

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Fast C-type inactivation confers distinctive functional properties to the hERG potassium channel, and its association to inherited and acquired cardiac arrythmias makes the study of the inactivation mechanism of hERG at the atomic detail of paramount importance. At present, two models have been proposed to describe C-type inactivation in K+-channels. Experimental data and computational work on the bacterial KcsA channel support the hypothesis that C-type inactivation results from a closure of the selectivity filter that sterically impedes ion conduction. Alternatively, recent experimental structures of a mutated Shaker channel revealed a widening of the extracellular portion of the selectivity filter, which might diminish conductance by interfering with the mechanism of ion permeation. Here, we performed molecular dynamics simulations of the wild-type hERG, a non-inactivating mutant (hERG-N629D), and a mutant that inactivates faster than the wild-type channel (hERG-F627Y) to find out which and if any of the two reported C-type inactivation mechanisms applies to hERG. Closure events of the selectivity filter were not observed in any of the simulated trajectories but instead, the extracellular section of the selectivity filter deviated from the canonical conductive structure of potassium channels. The degree of widening of the potassium binding sites at the extracellular entrance of the channel was directly related to the degree of inactivation with hERG-F627Y > wild-type hERG > hERG-N629D. These findings support the hypothesis that C-type inactivation in hERG entails a widening of the extracellular entrance of the channel rather than a closure of the selectivity filter.

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“…al may largely plastic the cellular ion homeostasis. The mechanism of C-type inactivation 24–26 and N-type inactivation 27,28 has some examples. However, the delayed rectifier activation coupled with the Cole-Moore effects remains elusive 3 .…”

Section: Discussionmentioning

confidence: 99%

“…al may largely plastic the cellular ion homeostasis. The mechanism of C-type inactivation [24][25][26] and N-type inactivation 27,28 has some examples.…”

Section: Mechanism Of Delayed Rectifier and Cole-moore Effectsmentioning

confidence: 99%

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel

Pei

Zhang

Shan

2023

Preprint

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Voltage gradient is a general physical cue that regulates diverse biological function through voltage-gated ion channels. How voltage sensing mediates ion flows remains unknown at the molecular level. Here, we report six conformations of the human Eag2 (hEag2) ranging from closed, pre-open, open, and pore dilation but non-conducting states captured by cryo-electron microscopy (cryo-EM). These multiple states illuminate dynamics of selectivity filter and ion permeating pathway with delayed rectifier property and Cole-Moore effect at the atomic level. Mechanistically, a short S4-S5 linker is coupled with the constrict sites to mediate voltage transducing in a non-domain-swapped configuration, resulting transitions for constrict sites of F464s and Q472s from gating to open state stabilizing for voltage energy transduction. Meanwhile, an additional ion occupied at positions S6 potassium ion confers the delayed rectifier property and Cole-Moore effects. These results provide novel insight into voltage transducing and potassium current across membrane, and shed light on the long-sought Cole-Moore effects.

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Structural basis for C-type inactivation in a Shaker family voltage-gated K ⁺ channel

Cited by 43 publications

References 60 publications

Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Early Steps in C-Type Inactivation of the hERG Potassium Channel

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel

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Structural basis for C-type inactivation in a Shaker family voltage-gated K + channel

Cited by 43 publications

References 60 publications

Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Driving Forces underlying Selectivity Filter Gating in the MthK Potassium Channel

Early Steps in C-Type Inactivation of the hERG Potassium Channel

Mechanism underlying delayed rectifying in human voltage-mediated activation Eag2 channel

Contact Info

Product

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Structural basis for C-type inactivation in a Shaker family voltage-gated K ⁺ channel