High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation.
High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation.
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DOI：
10.1021/bi3009449
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发表时间：
2012-11-13
期刊：
影响因子：
2.9
通讯作者：
Delisle BP
中科院分区：
文献类型：
--
作者：
Burgess DE;Bartos DC;Reloj AR;Campbell KS;Johnson JN;Tester DJ;Ackerman MJ;Fressart V;Denjoy I;Guicheney P;Moss AJ;Ohno S;Horie M;Delisle BP
1型长QT综合征（LQT 1）综合征是由KCNQ 1的功能丧失突变引起的，KCNQ 1编码K+通道（Kv7.1），该通道是心脏中缓慢激活的延迟整流K+电流的基础。基因内风险分层表明，破坏孔中保守氨基酸残基的LQT 1突变是LQT 1相关心脏事件的独立风险因素。本研究的目的是确定这些高危突变功能丧失的可能分子机制。对LQT 1患者的广泛基因型-表型分析显示，T322 M-、T322 A-或G325 R-Kv 7.1赋予LQT 1相关心脏事件的高风险。这些突变与KCNE 1的异源表达表明它们产生了非功能性通道，并导致WT-Kv 7.1电流的显性负抑制。KcsA类似突变（T85 M-、T85 A-和G88 R-KcsA）的分子动力学模拟（MDS）表明，它们破坏了选择性过滤器中羰基氧原子的对称分布，从而破坏了快速K+渗透所需的强吸引力和K+-K+排斥力之间的平衡。我们得出结论，孔中的高风险LQT 1突变可能会破坏K+通道选择性过滤器的结构和物理特性。
Type 1 long QT syndrome (LQT1) syndrome is caused by loss-of-function mutations in the KCNQ1, which encodes the K+ channel (Kv7.1) that underlies the slowly activating delayed rectifier K+ current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss-of-function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confer a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated non-functional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamic simulations (MDS) of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K+-K+ repulsive forces required for rapid K+ permeation. We conclude high-risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K+ channel selectivity filter.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
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