A hydrophobic nexus at the PAS-cap/globular PAS/CNPhd interface tunes deactivation kinetics of hERG channels

Abstract

Slow deactivation is a critical biophysical property of human ether-à -go-go related gene (hERG) channels, mediating the cardiac current IKr during repolarization of the ventricular action potential. Disruption of interactions between the intracellular N-terminal Per-Arnt-Sim (PAS) and C-terminal cyclic nucleotide-binding homology (CNBh) domains can impair slow deactivation and is associated with long QT syndrome (LQTS). The PAS-cap (residues 1-25), an essential mediator of slow deactivation, is composed of an unstructured segment (residues 1-12) and an amphipathic α-helix (residues 13-25).