Evolutionary coupling analysis guides identification of mistrafficking-sensitive variants in cardiac K⁺ channels: Validation with hERG.

ABSTRACT: Loss of function (LOF) mutations of voltage sensitive K⁺ channel proteins hERG (Kv11.1) and KCNQ1 (Kv7.1) account for the majority of instances of congenital Long QT Syndrome (cLQTS) with the dominant molecular phenotype being a mistrafficking one resulting from protein misfolding. We explored the use of Evolutionary Coupling (EC) analysis, which identifies evolutionarily conserved pairwise amino acid interactions that may contribute to protein structural stability, to identify regions of the channels susceptible to misfolding mutations. Comparison with published experimental trafficking data for hERG and KCNQ1 showed that the method strongly predicts "scaffolding" regions of the channel membrane domains and has useful predictive power for trafficking phenotypes of individual va

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC9632996 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature