High-Risk Long QT Syndrome Mutations in the Kv7.1 (KCNQ1) Pore Disrupt the Molecular Basis for Rapid K+ Permeation
| Autor: | Seiko Ohno, David J. Tester, Pascale Guicheney, Isabelle Denjoy, Minoru Horie, Allison R. Reloj, Véronique Fressart, Don E. Burgess, Arthur J. Moss, Michael J. Ackerman, Daniel C. Bartos, Brian P. Delisle, Jonathan N. Johnson, Kenneth S. Campbell |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Risk Adolescent Romano-Ward Syndrome Long QT syndrome Mutation Missense KcsA potassium channel Sequence alignment Molecular Dynamics Simulation Biology medicine.disease_cause Biochemistry Article medicine Humans Missense mutation Amino Acid Sequence Child Loss function Genetics Mutation Middle Aged medicine.disease Potassium channel Cell biology Potassium Channels Voltage-Gated KCNQ1 Potassium Channel Potassium Female Heterologous expression Sequence Alignment |
| Zdroj: | Biochemistry. 51:9076-9085 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi3009449 |
| Popis: | 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-phenotype 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(+)-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. |
| Databáze: | OpenAIRE |
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