High-Risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation

详细信息    查看全文

• 作者：Don E. Burgess ; Daniel C. Bartos ; Allison R. Reloj ; Kenneth S. Campbell ; Jonathan N. Johnson ; David J. Tester ; Michael J. Ackerman ; V茅ronique Fressart ; Isabelle Denjoy ; Pascale Guicheney ; Arthur J. Moss ; Seiko Ohno ; Minoru Horie ; Brian P. Delisle
• 刊名：Biochemistry
• 出版年：2012
• 出版时间：November 13, 2012
• 年：2012
• 卷：51
• 期：45
• 页码：9076-9085
• 全文大小：624K
• 年卷期：v.51,no.45(November 13, 2012)
• ISSN：1520-4995

文摘

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1 gene, 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鈥損henotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confers a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated nonfunctional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamics simulations 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⁺鈥揔⁺ 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.