Perturbation of sodium channel structureby an inherited Long QT syndrome mutation

摘要

The cardiac voltage-gated sodium channel (naV1.5) underlies impulse conduction in the heart,and its depolarization-induced inactivation is essential in control of the duration of the QTinterval of the electrocardiogram. Perturbation of naV1.5 inactivation by drugs or inheritedmutation can underlie and trigger cardiac arrhythmias. The carboxy terminus has an importantrole in channel inactivation, but complete structural information on its predicted structuraldomain is unknown. Here we measure interactions between the functionally critical distalcarboxy terminus alpha-helix (H6) and the proximal structured EF-hand motif using transitionmetal ion fluorescence resonance energy transfer. We measure distances at three loci alongH6 relative to an intrinsic tryptophan, demonstrating the proximal–distal interaction in acontiguous carboxy terminus polypeptide. using these data together with the existing naV1.5carboxy terminus nuclear magnetic resonance structure, we construct a model of the predictedstructured region of the carboxy terminus. An arrhythmia-associated H6 mutant that impairsinactivation decreases fluorescence resonance energy transfer, indicating destabilization of thedistal–proximal intramolecular interaction. These data provide a structural correlation to thepathological phenotype of the mutant channel.