NMR analysis of KChIP4a reveals structural basis for control of surface expression of Kv4 channel complexes

作者：Schwenk Jochen; Zolles Gerd; Kandias Nikolaos G; Neubauer Isabel; Kalbacher Hubert; Covarrubias Manuel; Fakler Bernd; Bentrop Detlef^*

来源：Journal of Biological Chemistry, 2008, 283(27): 18937-18946.

DOI：10.1074/jbc.M800976200

Potassium channel-interacting proteins ( KChIPs) are EF-hand calcium-binding proteins of the recoverin/neuronal calcium sensor 1 family that co-assemble with the pore-forming Kv4 alpha-subunits and thus control surface trafficking of the voltage-gated potassium channels mediating the neuronal IA and cardiac I-to currents. Different from the other KChIPs, KChIP4a largely reduces surface expression of the Kv4 channel complexes. Using solution NMR we show that the unique N terminus of KChIP4a forms a 6-turn alpha-helix that is connected to the highly conserved core of the KChIP protein via a solvent-exposed linker. As identified by chemical shift changes, N-terminal alpha-helix and core domain of KChIP4a interact with each other through the same hydrophobic surface pocket that is involved in intermolecular interaction between the N-terminal helix of Kv4 alpha and KChIP in Kv4-KChIP complexes. Electro-physiological recordings and biochemical interaction assays of complexes formed by wild-type and mutant Kv4 alpha and KChIP4a proteins suggest that competition of these two helical domains for the surface groove is responsible for the reduced trafficking of Kv4- KChIP4a complexes to the plasma membrane. Surface expression of Kv4 complexes may thus be controlled by an auto-inhibitory domain in the KChIP subunit.

• 出版日期2008-7-4