Interactions between selectivity filter and pore helix control filter gating in the MthK channel.
Interactions between selectivity filter and pore helix control filter gating in the MthK channel.
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DOI：
10.1085/jgp.202213166
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发表时间：
2023-08-07
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Kassel等人表明，MthK钾通道和孔-螺旋突变体V55 E中的过滤器门控与选择性过滤器的加宽相关，并通过过滤器和孔-螺旋残基之间的特异性相互作用进行调节。K+通道的活性可能会受到C型失活的限制，这可能是由K+离子从选择性过滤器中解离而引起的，并由周围的侧链进行调节。虽然晶体学和计算研究将失活与KcsA通道中的“塌陷”选择性过滤器构象联系起来，但其他K+通道中选择性过滤器门控的结构基础尚不清楚。在这里，我们结合电生理记录与分子动力学模拟，研究选择性过滤门控模型钾通道MthK及其V55 E突变体（类似于KcsA E71）在孔螺旋。我们发现，MthK V55 E具有比WT沟道更低的开放概率，这是由于开放状态的稳定性降低以及更低的么正电导。模拟占这两个变量的原子尺度上，显示在V55 E的离子渗透被改变的E55侧链的两个不同的方向。在E55与D 64形成氢键（如在KcsA WT通道中）的“垂直”取向中，与MthK WT相比，过滤器显示出降低的电导。相反，在“水平”方向，K+电导更接近MthK WT的电导;尽管选择性过滤器稳定性降低，导致更频繁的失活。令人惊讶的是，MthK WT和V55 E中的失活与选择性过滤器的加宽相关，这与KcsA观察到的不同，并且回忆了失活通道的近期结构，表明钾通道家族中存在保守的失活途径。
Kopec et al. show that filter gating in the MthK potassium channel and the pore-helix mutant V55E is associated with widening of the selectivity filter and is modulated by specific interactions between filter and pore-helix residues. 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 the side chains that surround it. While 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 is less clear. Here, we combined electrophysiological recordings with molecular dynamics simulations, to study selectivity filter gating in the model potassium channel MthK and its V55E mutant (analogous to KcsA E71) in the pore-helix. We found that MthK V55E has a lower open probability than the WT channel, due to decreased stability of the open state, as well as a lower unitary conductance. Simulations account for both of these variables on the atomistic scale, showing that ion permeation in V55E is altered by two distinct orientations of the E55 side chain. In the “vertical” orientation, in which E55 forms a hydrogen bond with D64 (as in KcsA WT channels), the filter displays reduced conductance compared to MthK WT. In contrast, in the “horizontal” orientation, K+ conductance is closer to that of MthK WT; although selectivity filter stability is lowered, resulting in more frequent inactivation. Surprisingly, inactivation in MthK WT and V55E is associated with a widening of the selectivity filter, unlike what is observed for KcsA and reminisces recent structures of inactivated channels, suggesting a conserved inactivation pathway across the potassium channel family.
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