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.