Two N-terminal domains of Kv4 K+ channels regulate binding to and modulation by KChIP1

The family of calcium binding proteins called KChlPs associates with Kv4 family K+ channels and modulates their biophysical properties. Here, using mutagenesis and X-ray crystallography, we explore the interaction between Kv4 subunits and KChlP1. Two regions in the Kv4.2 N terminus, residues 7-11 and 71-90, are necessary for KChlP1 modulation and interaction with Kv4.2. When inserted into the Kv1.2 N terminus, residues 71-90 of Kv4.2 are also sufficient to confer association with KChlP1. To provide a structural framework for these data, we solved the crystal structures of Kv4.3N and KChlP1 individually. Taken together with the mutagenesis data, the individual structures suggest that that the Kv4 N terminus is required for stable association with KChlP1, perhaps through a hydrophobic surface interaction, and that residues 71-90 in Kv4 subunits form a contact loop that mediates the specific association of KChlPs with Kv4 subunits.