Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.
Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations.
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DOI：
10.1126/sciadv.aar2631
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发表时间：
2018-03
期刊：
影响因子：
13.6
通讯作者：
Sanders CR
中科院分区：
文献类型：
--
作者：
Huang H;Kuenze G;Smith JA;Taylor KC;Duran AM;Hadziselimovic A;Meiler J;Vanoye CG;George AL Jr;Sanders CR
长QT综合征相关的KCNQ1突变最常破坏该蛋白的稳定性，导致误传递和降解。导致人类KCNQ1通道功能丧失（LOF）或功能障碍的突变是导致危及生命的心律障碍——先天性长QT综合征（LQTS）易感性的原因。数百种KCNQ1突变已被确定，但导致功能受损的分子机制尚不清楚。我们研究了51个KCNQ1突变对电压传感器域（VSD）的影响，重点阐明了对细胞表面表达、蛋白质折叠和结构的影响。对于每个变异，运输到质膜的效率，蛋白酶体抑制的影响和蛋白质稳定性进行了分析。这些实验结果与通道功能数据相结合，为将每种突变分类为六种机制类别之一提供了基础，突出了导致通道功能障碍或LOF的机制的异质性。超过一半的KCNQ1 LOF突变被观察到破坏VSD结构的稳定性，通常伴随着蛋白酶体的误运输和降解，这一观察结果强调了突变诱导的膜蛋白不稳定可能是一种常见的人类疾病机制。最后，我们观察到5个有折叠缺陷的LQTS突变位点位于VSD S0螺旋上，它们与VSD其他片段的许多LOF突变位点相互作用。这些观察结果揭示了S0螺旋作为中心支架的关键作用，有助于组织和稳定KCNQ1 VSD，并且很可能是许多其他离子通道的相应结构域。
Long QT syndrome–associated mutations in KCNQ1 most often destabilize the protein, leading to mistrafficking and degradation. Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure. For each variant, the efficiency of trafficking to the plasma membrane, the impact of proteasome inhibition, and protein stability were assayed. The results of these experiments combined with channel functional data provided the basis for classifying each mutation into one of six mechanistic categories, highlighting heterogeneity in the mechanisms resulting in channel dysfunction or LOF. More than half of the KCNQ1 LOF mutations examined were seen to destabilize the structure of the VSD, generally accompanied by mistrafficking and degradation by the proteasome, an observation that underscores the growing appreciation that mutation-induced destabilization of membrane proteins may be a common human disease mechanism. Finally, we observed that five of the folding-defective LQTS mutant sites are located in the VSD S0 helix, where they interact with a number of other LOF mutation sites in other segments of the VSD. These observations reveal a critical role for the S0 helix as a central scaffold to help organize and stabilize the KCNQ1 VSD and, most likely, the corresponding domain of many other ion channels.
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