Structure of the Ternary Complex of the C-Terminus of the Voltage-Gated Sodium Channel (NaV) with Calmodulin (CaM) and Fibroblast Growth Factor Homologous Factor (FHF)

Abstract

Voltage-gated sodium channel 1.5 (NaV1.5) is the major sodium channel expressed in heart tissue and is responsible for the initial upstroke of the action potential. Calmodulin (CaM) and fibroblast growth factor homologous factor (FHF) have been reported to regulate the inactivation of NaV1.5 by interacting with the C-terminal domain (CTD) of NaV1.5. Clinical studies also correlate many mutations on the C-terminus of NaV1.5 with arrhythmogenic heart diseases such as long QT syndrome and Brugada syndrome. We have solved the ternary complex structure of NaV1.5CTD/CaM/FHF2B in the absence of calcium. The calcium-free structure shows the calcium-independent binding of calmodulin to the IQ motif of NaV1.5CTD. Strong interactions between NaV1.5CTD and FHF2B are also observed in this structure. Several disease-causing mutations of NaV1.5CTD are found within the regions interacting with FHF2B and calmodulin. We also identified a critical interaction between NaV1.5CTD and FHF2B that contributes to FHF-subtype specificity. The insight provided by this structure will help us to delineate the regulatory mechanisms of CaM and FHF on the voltage-gated sodium channel.