KV1.3 Interacts with a Calmodulin-Binding Tetraleucine Motif of KCNE4

The voltage-gated potassium (Kv) channel Kv1.3 participates in the leukocyte proliferation, activation, and apoptosis. Dysregulation of this channel is at the onset of several autoimmune diseases. Thus, Kv1.3 function is essential for the immune system response. KCNE 4, functions as a dominant negative regulatory subunit of the channel altering inactivation and inducing intracellular retention. Mutations in KCNE4 are linked to immune system dysfunction. The formation of Kv1.3-KCNE4 complexes has profound consequences for leukocyte physiology, but the molecular determinants implicated in the association are not yet known. We demonstrate that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy-terminal domain of this accessory protein. The signal functions as an interactive platform, in which Kv1.3 and Ca2+/calmodulin would compete for the KCNE4 interaction. We also propose a structural model for the oligomeric Kv1.3-KCNE4 complex. In silico structure and experimental data suggest that the KCNE4 interaction hides forward-trafficking signatures of Kv1.3 and provides a strong endoplasmic reticulum retention motif to the Kv1.3-KCNE4 complex. The oligomeric composition of the Kv1.3 channelosome fine-tunes the balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.