A helical region in the C terminus of small-conductance Ca²⁺-activated K⁺ channels controls assembly with Apo-calmodulin

Small conductance Ca²⁺-activated potassium (SK) channels underlie the afterhyperpolarization that follows the action potential in many types of central neurons. SK channels are voltage-independent and gated solely by intracellular Ca²⁺ in the submicromolar range. This high affinity for Ca²⁺ results from Ca²⁺-independent association of the SK α-subunit with calmodulin (CaM), a property unique among the large family of potassium channels. Here we report the solution structure of the calmodulin binding domain (CaMBD, residues 396-487 in rat SK2) of SK channels using NMR spectroscopy. The CaMBD exhibits a helical region between residues 423-437, whereas the rest of the molecule lacks stable overall folding. Disruption of the helical domain abolishes constitutive association of CaMBD with Ca²⁺ free CaM, and results in SK channels that are no longer gated by Ca²⁺. The results show that the Ca²⁺-independent CaM-CaMBD interaction, which is crucial for channel function, is at least in part determined by a region different in sequence and structure from other CaM-interacting proteins.