Aim: 

K_v1 (KCNQ1) potassium channels are members of the superfamily of voltage-gated K⁺ channels. The K _v7.1 pore-forming subunit interacts with the KCNE1 auxiliary subunits to form the slow I_KS K⁺ current which plays a major role in repolarizing the cardiac action potential. Mutations in either K_v7.1 or KCNE1 genes produce the long QT (LQT) syndrome, a life-threatening ventricular arrhythmia.

Methods: 

Using patch-clamp, crystallographic and biochemical techniques, we examined the biophysical and structural properties of two important gating modules of K_v7.1, the pore and the C-terminus.

Results and Conclusions: 

Here we show that long QT mutations located in K _v7.1 C-terminus impair calmodulin (CaM) binding which affects both channel gating and assembly. The mutations produce macroscopic inactivation and dramatically hinder channel assembly. KCNE1 forms a ternary complex with K_v7.1 and Ca²⁺ -CaM which prevents inactivation, facilitates channel assembly and mediates Ca²⁺ -sensitive stimulation of I_KS-current. The C-terminus proximal half associates with one CaM constitutively bound to each subunit where CaM is critical for proper folding of the whole intracellular domain. The distal half directs tetramerization, employing tandem coiled-coils. The first coiled-coil complex is dimeric that undergoes concentration-dependent self-association to form a dimer of dimers. The outer coiled-coil is parallel tetrameric, whose details have been elucidated based on 2.0 Å crystallographic data. Both coiled-coils act in a coordinate fashion to mediate the formation and stabilization of the tetrameric distal half. Functional studies including characterization of structure-based and LQT mutants prove the requirement for both modules and point to complex roles for these modules including folding, assembly, trafficking and regulation.