The dipeptidyl-aminopeptidase-like protein 6 is an integral voltage sensor-interacting beta-subunit of neuronal K(V)4.2 channels.
Auxiliary beta-subunits dictate the physiological properties of voltage-gated K(+) (K(V)) channels in excitable tissues. In many instances, however, the underlying mechanisms of action are poorly understood. The dipeptidyl-aminopeptidase-like protein 6 (DPP6) is a specific beta-subunit of neuronal K(V)4 channels, which may promote gating through interactions between the single transmembrane segment of DPP6 and the channel's voltage sensing domain (VSD). A combination of gating current measurements and protein biochemistry (in-vitro translation and co-immunoprecipitations) revealed preferential physical interaction between the isolated K(V)4.2-VSD and DPP6. Significantly weaker interactions were detected between DPP6 and K(V)1.3 channels or the K(V)4.2 pore domain. More efficient gating charge movement resulting from a direct interaction between DPP6 and the K(V)4.2-VSD is unique among the known actions of K(V) channel beta-subunits. This study shows that the modular VSD of a K(V) channel can be directly regulated by transmembrane protein-protein interactions involving an extrinsic beta-subunit. Understanding these interactions may shed light on the pathophysiology of recently identified human disorders associated with mutations affecting the dpp6 gene.
Dougherty
Kevin
K
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA.
Tu
Liwei
L
Deutsch
Carol
C
Covarrubias
Manuel
M
D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004594:Electrophysiology; D006801:Humans; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000737:chemistry* / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D021122:Protein Subunits; D051672:Shal Potassium Channels / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D051664:Kv1.3 Potassium Channel; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D021122:Protein Subunits; D051672:Shal Potassium Channels; C503535:DPP6 protein, human; D010447:Peptide Hydrolases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases