The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

The voltage‐dependent potassium (Kv) channel Kv1.3 regulates leukocyte proliferation, activation, and apoptosis, and altered expression of this channel is linked to autoimmune diseases. Thus, the fine‐tuning of Kv1.3 function is crucial for the immune system response. The Kv1.3 accessory protein, potassium voltage‐gated channel subfamily E (KCNE) subunit 4, acts as a dominant negative regulatory subunit to both enhance inactivation and induce intracellular retention of Kv1.3. Mutations in KCNE4 also cause immune system dysfunction. Although the formation of Kv1.3‐KCNE4 complexes has profound consequences for leukocyte physiology, the molecular determinants involved in the Kv1.3‐KCNE4 association are unknown. We now show that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy‐terminal domain of this accessory protein. This motif would function as an interaction platform, in which Kv1.3 and Ca 2+ /calmodulin compete for the KCNE4 interaction. Finally, we propose a structural model of the Kv1.3‐KCNE4 complex. Our experimental data and the in silico structure suggest that the KCNE4 interaction hides a forward‐trafficking motif within Kv1.3 in addition to adding a strong endoplasmic reticulum retention signature to the Kv1.3‐KCNE4 complex. Thus, the oligomeric composition of the Kv1.3 channelosome fine‐tunes the precise balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.—Sole, L., Roig, S. R., Sastre, D., Vallejo‐Gracia, A., Serrano‐Albarrás, A., Ferrer‐Montiel, A., Fernández‐Ballester, G., Tamkun, M. M., Felipe, A. The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3. FASEB J. 33, 8263–8279 (2019). www.fasebj.org